Substituted hydroxamic acids and uses thereof

ABSTRACT

This invention provides compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , G, n, p and q have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.

PRIORITY CLAIM

The present application is a continuation of U.S. patent application Ser. No. 12/803,170, filed Jun. 21, 2010 (pending), which claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/219,103, filed Jun. 22, 2009, which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compounds and methods for the selective inhibition of HDAC6. The present invention relates to compounds useful as HDAC6 inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

BACKGROUND OF THE INVENTION

Histone deacetylase 6 (HDAC6) is a member of a family of amidohydrolases commonly referred to as histone or lysine deacetylases (HDACs or KDACs) as they catalyze the removal of acetyl groups from the ε-amino group of lysine residues from proteins. The family includes 18 enzymes which can be divided in 3 main classes based on their sequence homology to yeast enzymes Rpd3 (Class I), Hda1 (Class II) and Sir2 (Class III). A fourth class was defined with the finding of a distinct mammalian enzyme—HDAC11 (reviewed in Yang, et al., Nature Rev. Mol. Cell Biol. 2008, 9:206-218 and in Saunders and Verdin, Oncogene 2007, 26(37):5489-5504). Biochemically, Class I (HDAC1, 2, 3, 8) and Class II (HDAC4, 5, 6, 7, 9, 10) and Class IV (HDAC11) are Zn²⁺-dependent enzymes, while Class III (SIRT1-7) are dependent on nicotinamide adenine dinucleotide (NAD⁺) for activity. Unlike all other HDACs, HDAC6 resides primarily in the cytosol, it has 2 functional catalytic domains and a carboxy-terminal Zn²⁺-finger ubiquitin binding domain that binds ubiquitinated misfolded proteins (Kawaguchi et al., Cell 2003, 115(6):727-738), ubiquitin (Boyaullt et al., EMBO J. 2006, 25(14): 3357-3366), as well as ubiquitin-like FAT10 modifier (Kalveram et al., J. Cell Sci. 2008, 121(24):4079-4088). Known substrates of HDAC6 include cytoskeletal proteins α-tubulin and cortactin; β-catenin which forms part of adherens junctions and anchors the actin cytoskeleton; the chaperone Hsp90; and the redox regulatory proteins peroxiredoxin (Prx) I and Prx II (reviewed in Boyault et al., Oncogene 2007, 26(37):5468-5476; Matthias et al., Cell Cycle 2008, 7(1):7-10; Li et al., J Biol. Chem. 2008, 283(19):12686-12690; Parmigiani et al., Proc. Natl. Acad. Sci. USA 2009, 105(28):9633-9638). Thus, HDAC6 mediates a wide range of cellular functions including microtubule-dependent trafficking and signaling, membrane remodeling and chemotactic motility, involvement in control of cellular adhesion, ubiquitin level sensing, regulation of chaperone levels and activity, and responses to oxidative stress. All of these functions may be important in tumorigenesis, tumor growth and survival as well as metastasis (Simms-Waldrip et al., Mol. Genet. Metabolism 2008, 94(3):283-286; Rodriguez-Gonzalez et al., Cancer Res. 2008, 68(8):2557-2560; Kapoor, Int. J. Cancer 2009, 124:509; Lee et al., Cancer Res. 2008, 68(18):7561-7569). Recent studies have shown HDAC6 to be important in autophagy, an alternative pathway for protein degradation that compensates for deficiencies in the activity of the ubiquitin proteasome system or expression of proteins prone to form aggregates and can be activated following treatment with a proteasome inhibitor (Kawaguchi et al., Cell 2003, 115(6):727-738; Iwata et al., J. Biol. Chem. 2005, 280(48): 40282-40292; Ding et al., Am. J. Pathol. 2007, 171:513-524, Pandey et al., Nature 2007, 447(7146):860-864). Although the molecular mechanistic details are not completely understood, HDAC6 binds ubiquitinated or ubiquitin-like conjugated misfolded proteins which would otherwise induce proteotoxic stress and then serves as an adaptor protein to traffic the ubiquitinated cargo to the microtubule organizing center using the microtubule network via its known association with dynein motor protein. The resulting perinuclear aggregates, known as aggresomes, are then degraded by fusion with lysosomes in an HDAC6- and cortactin-dependent process which induces remodeling of the actin cytoskeleton proximal to aggresomes (Lee et al., EMBO J. 2010, 29:969-980). In addition, HDAC6 regulates a variety of biological processes dependent on its association with the microtubular network including cellular adhesion (Tran et al., J. Cell Sci. 2007, 120(8):1469-1479) and migration (Zhang et al., Mol. Cell 2007, 27(2):197-213; reviewed in Valenzuela-Fernandez et al., Trends Cell. Biol. 2008, 18(6):291-297), epithelial to mesenchymal transition (Shan et al., J. Biol. Chem. 2008, 283(30):21065-21073), resistance to anoikis (Lee et al., Cancer Res. 2008, 68(18):7561-7569), epithelial growth factor-mediated Wnt signaling via β-catenin deacetylation (Li, et al., J. Biol. Chem. 2008, 283(19):12686-12690) and epithelial growth factor receptor stabilization by endocytic trafficking (Lissanu Deribe et al., Sci. Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. 2010, 285:11219-11226); all events that promote oncogenesis and metastasis (Lee et al., Cancer Res. 2008, 68(18):7561-7569). HDAC6 activity is known to be upregulated by Aurora A kinase in cilia formation (Pugacheva et al., Cell 2007, 129(7):1351-1363) and indirectly by farnesyl transferase with which HDAC6 forms a complex with microtubules (Zhou et al., J. Biol. Chem. 2009, 284(15): 9648-9655). Also, HDAC6 is negatively regulated by tau protein (Perez et al., J. Neurochem. 2009, 109(6):1756-1766).

Diseases in which selective HDAC6 inhibition could have a potential benefit include cancer (reviewed in Simms-Waldrip et al., Mol. Genet. Metabolism 2008, 94(3):283-286 and Rodriguez-Gonzalez et al., Cancer Res. 2008, 68(8):2557-2560), specifically: multiple myeloma (Hideshima et al., Proc. Natl. Acad. ScL USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al., Biochem. Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro et al., Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al., Cancer Res. 2008, 68(18):7561-7569); prostate cancer (Mellado et al., Clin. Trans. Onco. 2009, 11(1):5-10); pancreatic cancer (Nawrocki et al., Cancer Res. 2006, 66(7):3773-3781); renal cancer (Cha et al., Clin. Cancer Res. 2009, 15(3):840-850); and leukemias such as acute myeloid leukemia (AML) (Fiskus et al., Blood 2008, 112(7):2896-2905) and acute lymphoblastic leukemia (ALL) (Rodriguez-Gonzalez et al., Blood 2008, 112(11): Abstract 1923).

Inhibition of HDAC6 may also have a role in cardiovascular disease, i.e. cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury (Tannous et al., Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused by uropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008, 284(1):446-454); neurological diseases caused by accumulation of intracellular protein aggregates such as Huntington's disease (reviewed in Kazantsev et al., Nat. Rev. Drug Disc. 2008, 7(10):854-868; see also Dompierre et al., J. Neurosci. 2007, 27(13):3571-3583; Kozikowski et al., J. Med. Chem. 2007, 50:3054-3061) or central nervous system trauma caused by tissue injury, oxidative-stress induced neuronal or axomal degeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); and inflammation, including reduction of pro-inflammatory cytokine IL-1β (Carta et al., Blood 2006, 108(5):1618-1626), increased expression of the FOXP3 transcription factor, which induces immunosuppressive function of regulatory T-cells resulting in benefits in chronic diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, lupus and organ transplant rejection (reviewed in Wang et al., Nat. Rev. Drug Disc. 2009 8(12):969-981).

Given the complex function of HDAC6, selective inhibitors could have potential utility when used alone or in combination with other chemotherapeutics such as microtubule destabilizing agents (Zhou et al., J. Biol. Chem. 2009, 284(15): 9648-9655); Hsp90 inhibitors (Rao et al., Blood 2008, 112(5)1886-1893); inhibitors of Hsp90 client proteins, including receptor tyrosine kinases such as Her-2 or VEGFR (Bhalla et al., J. Clin. Oncol. 2006, 24(18S): Abstract 1923; Park et al., Biochem. Biophys. Res. Commun. 2008, 368(2):318-322), and signaling kinases such as Bcr-Abl, Akt, mutant FLT-3, c-Raf, and MEK (Bhalla et al., J. Clin. Oncol. 2006, 24(18S): Abstract 1923; Kamemura et al., Biochem. Biophys. Res. Commun. 2008, 374(1):84-89); inhibitors of cell cycle kinases Aurora A and Aurora B (Pugacheva et al., Cell 2007, 129(7):1351-1363; Park et al., J. Mol. Med. 2008, 86(1):117-128; Cha et al., Clin. Cancer Res. 2009, 15(3):840-850); EGFR inhibitors (Lissanu Deribe et al., Sci. Signal. 2009, 2(102): ra84; Gao et al., J. Biol. Chem. E-pub Feb. 4, 2010) and proteasome inhibitors (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005, 102(24):8567-8572) or other inhibitors of the ubiquitin proteasome system such as ubiquitin and ubiqutin-like activating (E1), conjugation (E2), ligase enzymes (E3, E4) and deubiquitinase enzymes (DUBs) as well as modulators of autophagy and protein homeostasis pathways. In addition, HDAC6 inhibitors could be combined with radiation therapy (Kim et al., Radiother. Oncol. 2009, 92(1):125-132.

Clearly, it would be beneficial to provide novel HDAC6 inhibitors that possess good therapeutic properties, especially for the treatment of proliferative diseases or disorders.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of Compounds of the Invention

The present invention provides compounds that are inhibitors of HDAC6, and are useful for the treatment of proliferative diseases or disorders. In one aspect the compounds of the invention are represented by formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3;

G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or -L₁-V₂-L₂-R³;

L₁ and L₂ are each independently unsubstituted or substituted C₁₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—.

V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—;

V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—;

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(A) is independently hydrogen, halo, or unsubstituted or substituted C₁₋₄ aliphatic;

each occurrence of R^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄ aliphatic;

R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

ring A is optionally further substituted with n occurrences of R²;

each occurrence of R² is independently halo, C₁₋₄ aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or a C₁₋₄ aliphatic substituted with R^(D), halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(B), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C); or two R² are taken together to form a 3-6 membered cycloaliphatic ring;

each occurrence of R^(B) is independently H or C₁₋₄ aliphatic; or two R^(B) on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O and S;

each occurrence of R^(C) is independently C₁₋₄ aliphatic;

each occurrence of R^(D) is independently 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

n is 0-4.

In another aspect the compounds of the invention are represented by formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3;

G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³, -L₂-V₂—R³, —V₁-L₁-V₂—R³, or -L₁-R³;

L₁ is unsubstituted or substituted C₁₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—;

L₂ is unsubstituted or substituted C₂₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—;

V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—;

V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—,

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(A) is independently hydrogen, fluoro, or unsubstituted or substituted C₁₋₄ aliphatic;

each occurrence of R^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄ aliphatic;

R¹ is hydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkyl, or C₁₋₄ fluoroalkyl;

ring A is optionally further substituted with n occurrences of R²;

each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or R^(D); or two R² are taken together to form a 3-6 membered cycloaliphatic ring;

each occurrence of R^(D) is independently unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

n is 0-4.

2. Compounds and Definitions

Compounds of this invention include those described generally for formula (I) above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.

As described herein, compounds of the invention may be optionally substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term “substitutable”, when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about −80° C. to about +40°, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient.

The phrase “one or more substituents”, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.

As used herein, the term “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound.

As used herein, the term “aromatic” includes aryl and heteroaryl groups as described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means an optionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon, or a cyclic C₁₋₁₂ hydrocarbon which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle”, “cycloaliphatic”, “cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groups include optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified, in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic”, used alone or as part of a larger moiety, refer to an optionally substituted saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 ring carbon atoms. In some embodiments, the cycloaliphatic group is an optionally substituted monocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms. Cycloaliphatic groups include, without limitation, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also include optionally substituted bridged or fused bicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy” refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which, is substituted with one or more halogen atoms. As used herein, the term “halogen” or “halo” means F, Cl, Br, or I. The term “fluoroaliphatic” refers to a haloaliphatic wherein the halogen is fluoro, including perfluorinated aliphatic groups. Examples of fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety, e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionally substituted C6-14aromatic hydrocarbon moiety comprising one to three aromatic rings. Preferably, the aryl group is a C6-10aryl group. Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl” may be used interchangeably with the terms “aryl group”, “aryl ring”, and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted. Preferably, the aralkyl group is C6-10 arylC1-6alkyl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. In some embodiments, the heteroaryl group has 5-10 ring atoms, having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. For example, a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 4-10 membered ring, preferably a 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. Additionally, a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH₂)_(n′)—, wherein n′ is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3-7-membered ring. The substituents can be on the same or different atoms.

An alkylene chain also can be optionally interrupted by a functional group. An alkylene chain is “interrupted” by a functional group when an internal methylene unit is interrupted by the functional group. Examples of suitable “interrupting functional groups” are described in the specification and claims herein.

For purposes of clarity, all bivalent groups described herein, including, e.g., the alkylene chain linkers described above, are intended to be read from left to right, with a corresponding left-to-right reading of the formula or structure in which the variable appears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be “optionally substituted”. In addition to the substituents defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group also include and are generally selected from -halo, —NO₂, —CN, —R⁺, —C(R⁺)═C(R⁺)₂, —C≡C—R⁺, —OR⁺, —SR^(o), —S(O)R^(o), —SO₂R^(o), —SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺, —NR⁺C(O)N(R⁺)₂, —NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺, —O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺, —C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺, —C(O)N(R⁺)₂, —C(S)N(R⁺)₂, —C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺, —N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺, —C(R^(o))═N—OR⁺, —P(O)(R⁺)₂, —P(O)(OR⁺)₂, —O—P(O)—OR⁺, and —P(O)(NR⁺)—N(R⁺)₂, wherein R⁺, independently, is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group, or two independent occurrences of R⁺ are taken together with their intervening atom(s) to form an optionally substituted 5-7-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Each R^(o) is an optionally substituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclyl group.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic or heterocyclic ring may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o)═N—NHSO₂R^(o) or ═N—R* where R^(o) is defined above, and each R* is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group.

In addition to the substituents defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring also include and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. A ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N-hydroxy or N-oxide compound. A nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences of R⁺ (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) to form a monocyclic or bicyclic ring selected from 3-13-membered cycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺ (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) include, but are not limited to the following: a) two independent occurrences of R⁺ (or any other variable similarly defined in the specification or claims herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺ are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R⁺ (or any other variable similarly defined in the specification or claims herein) that are bound to different atoms and are taken together with both of those atoms to form a ring,

for example where a phenyl group is substituted with two occurrences of OR these two occurrences of R⁺ are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., spiro and bridged rings) can be formed when two independent occurrences of R+ (or any other variable similarly defined in the specification and claims herein) are taken together with their intervening atom(s) and that the examples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

The terms “stereoisomer”, “enantiomer”, “diastereomer”, “epimer”, and “chiral center”, are used herein in accordance with the meaning each is given in ordinary usage by those of ordinary skill in the art. Thus, stereoisomers are compounds that have the same atomic connectivity, but differ in the spatial arrangement of the atoms. Enantiomers are stereoisomers that have a mirror image relationship, that is, the stereochemical configuration at all corresponding chiral centers is opposite. Diastereomers are stereoisomers having more than one chiral center, which differ from one another in that the stereochemical configuration of at least one, but not all, of the corresponding chiral centers is opposite. Epimers are diastereomers that differ in stereochemical configuration at only one chiral center.

It is to be understood that, when a disclosed compound has at least one chiral center, the present invention encompasses one enantiomer of the compound, substantially free from the corresponding optical isomer, a racemic mixture of both optical isomers of the compound, and mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a mixture is enriched in one enantiomer relative to its optical isomer, the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95%, 99%, or 99.5%.

The enantiomers of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the present invention encompasses a diastereomer substantially free of other diastereomers, an enantiomeric pair of diastereomers substantially free of other stereoisomers, mixtures of diastereomers, mixtures of enantiomeric pairs of diastereomers, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), and mixtures of enantiomeric pairs of diastereomers in which one enantiomeric pair of diastereomers is enriched relative to the other stereoisomers. When a mixture is enriched in one diastereomer or enantiomeric pair of diastereomers pairs relative to the other stereoisomers, the mixture is enriched with the depicted or referenced diastereomer or enantiomeric pair of diastereomers relative to other stereoisomers for the compound, for example, by a molar excess of at least 50%, 75%, 90%, 95%, 99%, or 99.5%.

As used herein, the term “diastereomeric ratio” refers to the ratio between diastereomers which differ in the stereochemical configuration at one chiral center, relative to a second chiral center in the same molecule. By way of example, a chemical structure with two chiral centers provides four possible stereoisomers: R*R, R*S, S*R, and S*S, wherein the asterisk denotes the corresponding chiral center in each stereoisomer. The diastereomeric ratio for such a mixture of stereoisomers is the ratio of one diastereomer and its enantiomer to the other diastereomer and its enantiomer=(R*R+S*S):(R*S+S*R).

One of ordinary skill in the art will recognize that additional stereoisomers are possible when the molecule has more than two chiral centers. For purposes of the present invention, the term “diastereomeric ratio” has identical meaning in reference to compounds with multiple chiral centers as it does in reference to compounds having two chiral centers. Thus, the term “diastereomeric ratio” refers to the ratio of all compounds having R*R or S*S configuration at the specified chiral centers to all compounds having R*S or S*R configuration at the specified chiral centers. For convenience, this ratio is referred to herein as the diastereomeric ratio at the asterisked carbon, relative to the second specified chiral center.

The diastereomeric ratio can be measured by any analytical method suitable for distinguishing between diastereomeric compounds having different relative stereochemical configurations at the specified chiral centers. Such methods include, without limitation, nuclear magnetic resonance (NMR), gas chromatography (GC), and high performance liquid chromatography (HPLC) methods.

The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of compounds disclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In some embodiments, for compounds of formula (I):

V₁ is —C(O)—, —C(O)—N(R^(4a)), or —S(O)₂—;

V₂ is —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or —S—; and

n is 0-2.

In some embodiments, for compounds of formula (I):

R¹ is hydrogen or methyl;

each occurrence of R² is independently fluoro, methyl, or trifluoromethyl;

V₁ is —C(O)—, —C(O)—N(R^(4a)), or —S(O)₂—;

V₂ is —C(O)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or —S—; and

n is 0-2.

In some embodiments, for compounds of formula (I):

R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R³ when substituted is substituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d), -T₁-R^(5d), or —V₃-L₃-R^(5d);

each occurrence of R^(5a) is independently halogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd), halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂;

each occurrence of R^(5b) is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R^(5b) on the same nitrogen atom can be taken together with the nitrogen atom to which they are bound to form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5c) is independently an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5d) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5dd) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each occurrence of R^(5e) is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group;

each occurrence of V₃ is independently —N(R^(5e)), —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(5e))—, —S(O)₂N(R^(5e))—, —OC(O)N(R^(5e))—, —N(R^(5e))C(O)—, —N(R^(5e))SO₂—, —N(R^(5e))C(O)O—, —N(R^(5e))C(O)N(R^(5e))—, —N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or —C(O)N(R^(5e))O—; and

L₃ is an optionally substituted C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—.

In some embodiments, compounds of formula (I) are represented by formulas (II-A)-(II-F):

wherein R¹, R², G, and n have the values described herein.

In some embodiments, compounds of formula (I) are represented by formulas (II-A), (II-B), or (II-C). In some embodiments, compounds of formula (I) are represented by formulas (II-A), or (II-B). In certain embodiments, compounds of formula (I) are represented by formula (II-A). In certain embodiments, compounds of formula (I) are represented by formula (II-B).

In some embodiments, compounds of formula (I) are represented by formulas (III-A)-(III-F):

wherein G, and R¹ have the values described herein.

In some embodiments, compounds of formula (I) are represented by formulas (III-A), (III-B), or (III-C). In some embodiments, compounds of formula (I) are represented by formulas (III-A), or (III-B). In certain embodiments, compounds of formula (I) are represented by formula (III-A). In certain embodiments, compounds of formula (I) are represented by formula (III-B).

In some embodiments, compounds of formula (I) are represented by formulas (IV-A)-(IV-C):

wherein G has the values described herein.

In certain embodiments, compounds of formula (I) are represented by formula (IV-A). In certain embodiments, compounds of formula (I) are represented by formula (IV-B). In certain embodiments, compounds of formula (I) are represented by formula (IV-C).

In some embodiments, compounds of formula (I) are represented by formulas (V-A)-(V-G):

wherein R³, R⁶, R^(6′), p, q, and V_(2a) have the values described herein.

In certain embodiments, compounds of formula (I) are represented by formula (V-A). In certain embodiments, compounds of formula (I) are represented by formula (V-B). In certain embodiments, compounds of formula (I) are represented by formula (V-C). In certain embodiments, compounds of formula (I) are represented by formula (V-D). In certain embodiments, compounds of formula (I) are represented by formula (V-E). In certain embodiments, compounds of formula (I) are represented by formula (V-F). In certain embodiments, compounds of formula (I) are represented by formula (V-G).

The values described below are with respect to any of formulas (I), (II-A)-(II-G), (III-A)-(III-G), (IV-A)-(IV-B) and (V-A)-(V-G).

In some embodiments:

p is 0-2;

q is 1-3;

provided that the total of p and q is 1-3.

In certain embodiments, p is 1 and q is 1. In certain embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and q is 2. In certain embodiments, p is 1 and q is 2. In certain embodiments, p is 2 and q is 1. In certain embodiments, p is 0 and q is 3.

In some embodiments, R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl. In some embodiments, R¹ is hydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkyl, or C₁₋₄ fluoroalkyl. In certain embodiments, R¹ is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl. In certain embodiments, R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl. In certain embodiments, R¹ is hydrogen or methyl. In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ is methyl.

In some embodiments, ring A is optionally further substituted with n occurrences of R² wherein, each occurrence of R² is independently halo, C₁₋₄ aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or a C₁₋₄ aliphatic substituted with R^(D), halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C). In some embodiments, two R² are, taken together to form a 3-6 membered cyclaliphatic ring. In some embodiments, each occurrence of R² is independently halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, NHS(O)₂C₁₋₃ alkyl; or C₁₋₄aliphatic optionally substituted with R^(D). In certain embodiments, each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy, propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

In some embodiments, each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, —NHC(O)C₁₋₆ alkyl, —NHC(O)NHC₁₋₆ alkyl, NHS(O)₂C₁₋₆ alkyl, or R^(D), wherein R^(D) has the values contained herein. In some embodiments, each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or R^(D), wherein R^(D) has the values contained herein. In some embodiments each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄haloalkyl, or phenyl, wherein the phenyl ring is unsubstituted or substituted with one occurrence of fluoro, chloro, or methyl. In some embodiments, each occurrence of R² is independently fluoro, methyl, or trifluoromethyl. In certain embodiments, each occurrence of R² is independently methyl or fluoro. In certain embodiments, R² is methyl.

In some embodiments, each occurrence of R^(B) is independently H or C₁₋₄ aliphatic; or two R^(B) on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O and S.

In some embodiments, each occurrence of R^(C) is independently C₁₋₄ aliphatic.

In some embodiments, each occurrence of R^(D) is independently 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, n is 0-4. In some embodiments, n is 0-2. In certain embodiments, n is 2. In certain embodiments, n is 1. In certain embodiments, n is 0.

In some embodiments, G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or -L₁-V₂-L₂-R³, wherein L₁, L₂, V₁, V₂, and R³ have the values described herein. In some embodiments, G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³, -L₂-V₂—R³, —V₁-L₁-V₂—R³, or -L₁-R³, wherein L₁, L₂, V₁, V₂, and R³ have the values described herein. In some embodiments, G is —R³, —V₁—R³, or -L₁-R³, wherein L₁, V₁, and R³ have the values described herein.

In certain embodiments, G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³, wherein R³, R⁶, and R^(6′) have the values described herein. In certain embodiments, G is —R³, wherein R³ has the values described herein. In certain embodiments, G is —(CH₂)_(t)—R³, or —(CH₂)_(t)—X₃—R³, wherein R³, X₃ and t have the values described herein. In certain embodiments, G is —C(O)—R³, —C(R⁶)(R^(6′))—R³, —C(O)—C(R⁶)(R^(6′))—R³, —S(O)₂—R³, —S(O)₂—C(R⁶)(R^(6′))—R³, or —C(O)—NH—R³, wherein R³, R⁶ and R^(6′) have the values described herein. In certain embodiments, G is —CH₂—CH═CH—R³, wherein R³ has the values described herein.

In certain embodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—N(R^(4a))—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, —[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³, wherein R⁶, R^(6′), V_(2a), V_(2a′), R³, R^(4a), z, and y have the values described herein. In certain embodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, —[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³, wherein R⁶, R^(6′), V_(2a), V_(2a′), R³, z, and y have the values described herein. In certain embodiments, G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, or —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, wherein R⁶, R^(6′), R³, and z have the values described herein.

In some embodiments, L₁ and L₂ are each independently unsubstituted or substituted C₁₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—. In some embodiments, L₁ and L₂ are each independently —CH₂—, CH₂CH₂—, —CH₂CH₂CH₂—, or —CH═CH—. In some embodiments, L₁ and L₂ are each independently —CH₂—. In some embodiments, L₁ and L₂ are each independently a C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2 occurrences of R^(8a) wherein each occurrence of R^(8a) is independently halogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5e), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂; or a C₁₋₄ aliphatic substituted with halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂. In some embodiments, L₁ and L₂ are each independently a C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2 occurrences of R^(8a) wherein each occurrence of R^(8a) is independently fluoro or C₁₋₄ aliphatic.

In some embodiments, L₂ is unsubstituted or substituted C₂₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—. In some embodiments, L₂ is —CH₂CH₂— or —CH₂CH₂CH₂—. In certain embodiments, L₂ is —CH₂CH₂—. In certain embodiments, L₂ is —CH₂CH₂CH₂—.

In some embodiments, V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—, wherein R^(4a) has the values described herein. In some embodiments, V₁ is —C(O)—, —C(O)—N(R^(4a))—, or S(O)₂—, wherein R^(4a) has the values described herein. In certain embodiments, V₁ is —C(O)—, —C(O)—NH—, or S(O)₂—. In certain embodiments, V₁ is —C(O)—, or S(O)₂—.

In some embodiments, V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—, wherein R^(4a) has the values described herein. In some embodiments, V₂ is —C(O)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or —S—. In certain embodiments, V₂ is —C(O)—, —N(R^(4a))—, —O—, or —S—. In certain embodiments, V₂ is —NH—, or —O—.

In some embodiments, each occurrence of R^(A) is independently hydrogen, halo, or an unsubstituted or substituted C₁₋₄aliphatic. In some embodiments, each occurrence of R^(A) is independently hydrogen, fluoro, or unsubstituted or substituted C₁₋₄ aliphatic. In certain embodiments, each occurrence of R^(A) is independently hydrogen, fluoro or methyl. In certain embodiments, each occurrence of R^(A) is hydrogen.

In some embodiments, each occurrence of R^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄aliphatic. In some other embodiments, each occurrence of R^(4a) is independently hydrogen.

In some embodiments, G is represented by formulas (VI-a-i)-(VI-n-v):

In some embodiments, R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl, pentenyl, hexenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydronaphthyridinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or adamantyl, wherein each of the foregoing groups are unsubstituted or substituted.

In some embodiments, R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein if R³ is substituted, it is substituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d), -L₃-R^(5d), —V₃-L₃-R^(5d); and R^(5a), R^(5d), L₃, and V₃ have the values described herein.

In certain embodiments, R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl, pentenyl, hexenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydronaphthyridinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or adamantyl, wherein each of the foregoing groups are unsubstituted or substituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d), -L₃-R^(5d), or —V₃-L₃-R^(5d); and R^(5a), R^(5d), L₃, and V₃ have the values described herein.

In some embodiments, R³ is —R^(3a), wherein R^(3a) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R^(3a) if substituted is substituted with 0-1 occurrences of —R^(5a), and one occurrence of —R^(5d), wherein R^(5a) and R^(5d) have the values described herein.

In some embodiments, R^(3a) is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or pteridinyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrences of —R^(5a), and 1 occurrence of —R^(5d), wherein R^(5a) and R^(5d) have the values described herein. In certain embodiments, R^(3a) is thienyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, 4H-furo[3,2-b]pyrrolyl, or phenyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrences of —R^(5a), and 1 occurrence of —R^(5d), wherein R^(5a) and R^(5d) have the values described herein.

In some embodiments, R³ is —R^(3b), wherein R^(3b) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R^(3b) if substituted is substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein. In some embodiments, R^(3b) is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or pteridinyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrence of —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, R³ is —R^(3c), wherein R^(3c) is unsubstituted or substituted 6-10-membered aryl, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3c) if substituted is substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein. In some embodiments, R^(3c) is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, quinuclidinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, or chromanyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein. In certain embodiments, R^(3c) is phenyl, naphthyl or indolyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, R³ is —R^(3d), wherein R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3d) if substituted is substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, wherein R^(3d) if substituted is substituted with 0-1 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein. In certain embodiments, R^(3d) is methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl, pentenyl, or hexenyl.

In some embodiments, R^(3d) is unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3d) if substituted is substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein. In certain embodiments, R^(3d) is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, quinuclidinyl, indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or adamantyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-2 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein.

In certain embodiments, R^(3d) is pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, phenyl, pyridyl, indolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, purinyl, quinolyl, cinnolinyl, naphthyl, piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, or adamantyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 independent occurrences of —R^(5a), wherein R^(5a) has the values described herein.

In some embodiments, each occurrence of R^(5a) is independently halogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd), halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂, wherein R^(5b), R^(5c), R^(5dd), and R^(5e) have the values described herein.

In some embodiments, R^(5a) is halo, C₁₋₃alkyl, C₁₋₃haloalkyl, —O—C₁₋₃alkyl, —O—C₁₋₃ haloalkyl, —C(O)C₁₋₃ alkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl. In some embodiments, R^(5a) is —CH₂—R^(5dd), wherein R^(5dd) is phenyl, pyridyl, naphthyl or thienyl optionally substituted with 0-1 occurrence of R^(7a), wherein R^(7a) has the values described herein. In certain embodiments, R^(5a) is chloro, fluoro, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, butyl, isopropyl, —NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)NHCH₃, or —NHS(O)₂CH₃.

In some embodiments, each occurrence of R^(5a) is independently chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl. In certain embodiments, each occurrence of R^(5a) is chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.

In some embodiments, each occurrence of R^(5b) is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R^(5b) on the same nitrogen atom can be taken together with the nitrogen atom to which they are bound to form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, each occurrence of R^(5c) is independently an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each occurrence of R^(5e) is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group. In some other embodiments, each occurrence of R^(5e) is independently hydrogen.

In some embodiments, the variable R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl. In some embodiments, R⁶ is hydrogen, C₁₋₄ aliphatic, or C₃₋₆ cycloaliphatic. In certain embodiments, R⁶ is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R⁶ is hydrogen or methyl. In certain embodiments, R⁶ is hydrogen.

In some embodiments, the variable R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl. In some embodiments, R^(6′) is hydrogen, C₁₋₄ aliphatic, or C₃₋₆ cycloaliphatic. In certain embodiments, R^(6′) is hydrogen, methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R^(6′) is hydrogen or methyl. In certain embodiments, R^(6′) is hydrogen.

In some embodiments, R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group. In certain embodiments, R⁶ and R^(6′) are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

In some embodiments, V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—. In certain embodiments, V_(2a) is —NH— or —O—.

In some embodiments, V_(2a′) is —O—, —S—, or —N(R^(4a))—, wherein R^(4a) has the values described herein. In certain embodiments, V_(2a′) is —O— or —NH—.

In some embodiments, t is 2-3. In certain embodiments, t is 2. In certain embodiments, t is 3.

In some embodiments, u is 2-3. In certain embodiments, u is 2. In certain embodiments, u is 3.

In some embodiments, z is 0-3. In some embodiments, z is 0-1. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3.

In some embodiments, y is 2-3. In certain embodiments, y is 2. In certain embodiments, y is 3.

In some embodiments, V₃ is —N(R^(5e)), —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(5e))—, —S(O)₂N(R^(5e))—, —OC(O)N(R^(5e))—, —N(R^(5e))C(O)—, —N(R^(5e))SO₂—, —N(R^(5e))C(O)O—, —N(R^(5e))C(O)N(R^(5e))—, —N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or —C(O)N(R^(5e))O—. In some embodiments, V₃ is —N(R^(5e)), —O—, —S—, —C(O)—, —C(O)O—, —C(O)N(R^(5e))—, or —S(O)₂N(R^(5e)). In some embodiments, V₃ is —NH—, —O—, —S—, or —C(O)—.

In some embodiments, L₃ is an optionally substituted C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—. In some embodiments, L₃ is —CH₂—, CH₂CH₂—, —CH₂CH₂CH₂—, or —CH═CH—. In some embodiments, L₃ is —CH₂—. In some embodiments, L₃ is a C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2 occurrences of R^(8a), wherein each occurrence of R^(8a) is independently halogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c), —C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5c), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂; or two occurrences of R^(5b) on the same nitrogen atom taken together with the nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; wherein R^(5b), R^(5c) and R^(5e) have the values described herein. In some embodiments, L₃ is a C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—, optionally substituted with 0-2 occurrences of R^(8a), wherein each occurrence of R^(8a) is independently fluoro or C₁₋₄ aliphatic.

In some embodiments, R^(5d) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R^(5d) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(5d) if substituted, is substituted with 0-2 independent occurrences of —R^(7a), wherein R^(7a) has the values described herein. In some embodiments, R^(5d) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(5d) if substituted is substituted with 0-1 independent occurrences of R^(7a), wherein R^(7a) has the values described herein.

In some embodiments, R^(5d) is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl, isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, or pteridinyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-2 independent occurrences of —R^(7a), wherein R^(7a) has the values described herein. In certain embodiments, R^(5d) is thienyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl, or benzothienyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrences of —R^(7a), wherein R^(7a) has the values described herein. In certain embodiments, R^(5d) is thienyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl, pyrimidinyl, or benzothienyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrences of —R^(7a), wherein R^(7a) has the values described herein.

In some embodiments, R^(5dd) is R^(5d). In some other embodiments, R^(5dd) is phenyl, pyridyl, naphthyl or thienyl, wherein each of the foregoing groups is unsubstituted or substituted with 0-1 occurrence of R^(7a), wherein R^(7a) has the values described herein.

In some embodiments, R^(7a) is halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl. In some embodiments, R^(7a) is chloro, fluoro, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, —NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)NHCH₃, or —NHS(O)₂CH₃. In some embodiments, each occurrence of R^(7a) is chloro, fluoro, bromo, iodo, C₁₋₆ alkyl, C₁₋₆fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl. In certain embodiments, R^(7a) is chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.

In certain embodiments:

G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3a); and

R^(3a) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R^(3a) if substituted is substituted with 0-1 occurrences of —R^(5a), and one occurrence of —R^(5d);

wherein R^(5a) and R^(5d) have the values described herein.

In certain embodiments:

G is —R³;

R³ is —R^(3b); and

R^(3b) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R^(3b) if substituted is substituted with 0-2 independent occurrences of —R^(5a);

wherein R^(5a) has the values described herein.

In certain embodiments:

G is —(CH₂)_(t)—R³ or —(CH₂)_(t)—V_(2a)—R³;

R³ is —R^(3c);

R^(3c) is unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3a) if substituted is substituted with 0-2 independent occurrences of —R^(5a);

V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—; and

t is 2-3;

wherein R^(5a) and R^(4a) have the values described herein.

In certain embodiments:

G is —C(R⁶)(R^(6′))—R³, —C(O)—[C(R⁶)(R^(6′))]_(u)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(u)—R³, or —C(O)—NH—[(R⁶)(R^(6′))]_(u)—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3d);

R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R^(3d) if substituted is substituted with 0-2 independent occurrences of —R^(5a); and

u is 1-2;

wherein R^(5a) has the values described herein.

In certain embodiments, the compound of formula (I) is represented by formulas (II-A)-(II-B):

wherein:

each occurrence of R¹ is independently chloro, fluoro, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl;

each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy, propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl;

n is 0-2;

R^(5a) is halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

R^(5d) is optionally substituted with 0-2 occurrences of —R^(7a); and

each occurrence of R^(7a) is independently halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

wherein G has the values described herein.

In certain embodiments, the compound of formula (I) is represented by formula (II-C):

wherein:

each occurrence of R¹ is independently chloro, fluoro, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl;

each occurrence of R² is independently chloro, fluoro, methoxy, ethoxy, propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or tert-butyl;

n is 0-2;

R^(3d) is optionally substituted with 0-1 occurrences of —R^(5a); and

each occurrence of R^(5a) is independently halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl;

wherein G has the values described herein.

In certain embodiments, the compound of formula (I) is represented by formula (II-A)-(II-C):

wherein:

G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³;

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

R³ is —R^(3a); and

R^(3a) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3a) if substituted is substituted with 0-1 occurrences of —R^(5a), and one occurrence of —R^(5d);

wherein R¹, R², R^(5a), R^(5d), and n have the values described herein.

In certain embodiments, described directly above:

R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl;

each occurrence of R² is independently fluoro, methyl, or trifluoromethyl;

n is 0-2;

R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl;

R^(5d) if substituted is substituted with 0-2 occurrences of —R^(7a); and

each occurrence of R^(7a) is independently chloro, fluoro, bromo, iodo, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl;

wherein R^(5d) has the values described herein.

In certain embodiments, the compound of formula (I) is represented by formula (II-A)-(II-C):

wherein:

G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, —[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a′)—R³,

R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl;

R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or

R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group;

V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—;

V_(2a′) is —O—, —S—, or —N(R^(4a))—;

R³ is —R^(3d);

R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3d) if substituted is substituted with 0-2 independent occurrences of —R^(5a);

z is 0-3; and

y is 1-2;

wherein R¹, R², R^(5a), and n have the values described herein.

In certain embodiments, described directly above:

R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl;

each occurrence of R² is independently fluoro, methyl, or trifluoromethyl;

n is 0-2;

R^(3d) is unsubstituted or substituted with 0-1 occurrences of —R^(5a); and

R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl;

wherein R^(5d) has the values described herein.

Representative examples of compounds of formula (I) are shown in Table 1:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

The compounds in Table 1 above may also be identified by the following chemical names:

1 6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 2 6-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 3 N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 4 6-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 5 N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 6 N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 7 6-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 8 N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 9 6-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 10 6-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 11 N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 12 6-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 13 6-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 14 6-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 15 N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 16 N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 17 6-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 18 6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 19 6-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 20 6-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 21 N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 22 6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tefrahydrothieno[2,3-c]pyridine-2- carboxamide 23 N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 24 N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 25 6-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 26 5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 27 N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 28 N-hydroxy-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 29 N-hydroxy-5-[(5-methylpyrazin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 30 N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 31 5-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 32 5-[4-(4,6-dimethoxypyrimidin-2-yl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 33 5-(1-adamantylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 34 N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 35 5-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 36 6-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 37 N-hydroxy-5-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 38 N-hydroxy-5-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 39 5-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 40 N²-hydroxy-N⁶-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 41 N-hydroxy-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 42 6-(2-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 43 N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-methyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 44 6-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 45 N⁵-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 46 5-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 47 6-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 48 N-hydroxy-6-[(2-methyl-4-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 49 N-hydroxy-4-methyl-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 50 N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2- carboxamide 51 6-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 52 6-[(3,5-difluorophenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 53 N-hydroxy-5-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 54 N²-hydroxy-N⁶-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 55 N²-hydroxy-N⁵-(3-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 56 6-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 57 6-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 58 6-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 59 N-hydroxy-6-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 60 N⁵-(4-chlorobenzyl)-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 61 N⁵-[(1S)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 62 6-[(3,5-dimethylisoxazol-4-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 63 N²-hydroxy-N⁶-(4-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 64 6-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 65 N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 66 5-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 67 6-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 68 N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 69 6-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 70 N-hydroxy-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 71 6-[(4′-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 72 6-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 73 N-hydroxy-5-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 74 N⁵-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 75 N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 76 N⁶-cyclohexyl-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 77 N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 78 5-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 79 N²-hydroxy-N⁶-(3-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 80 N²-hydroxy-N⁶-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 81 N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 82 5-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 83 5-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 84 N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 85 N-hydroxy-6-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 86 N⁶-[2-fluoro-4-(trifluoromethyl)phenyl]-N²-hydroxy-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 87 6-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 88 6-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 89 N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 90 N¹⁰-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-4,5,6,7,8,9-hexahydro-4,8- epiminocycloocta[b]thiophene-2,10-dicarboxamide 91 N-hydroxy-6-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 92 10-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8- epiminocycloocta[b]thiophene-2-carboxamide 93 N-hydroxy-6-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 94 N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 95 N-hydroxy-6-(quinolin-6-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 96 N-hydroxy-5-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 97 5-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 98 N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 99 N-hydroxy-6-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 100 6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 101 N-hydroxy-5-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 102 N-hydroxy-6-({5-{3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 103 N²-hydroxy-N⁶-(4-methylbenzyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 104 10-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epiminocycloocta[b]thiophene-2- carboxamide 105 N-hydroxy-5-[4-(trifluoromethyl)benzyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 106 N⁶-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 107 N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 108 6-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 109 N²-hydroxy-N⁵-(4-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 110 6-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 111 N-hydroxy-6-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 112 6-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 113 5-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 114 6-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 115 5-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 116 N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 117 N⁶-[4-chloro-3-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 118 6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 119 N-hydroxy-7,7-dimethyl-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 120 N-hydroxy-6-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 121 6-[(4-tert-butylphenyl)sulfonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 122 6-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 123 6-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 124 5-[(4′-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 125 6-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 126 N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 127 N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 128 6-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 129 N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 130 N-hydroxy-6-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 131 6-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 132 N²-hydroxy-N⁶-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 133 N-hydroxy-6-[3-(1H-pyrazol-1-yl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 134 6-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 135 N-hydroxy-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 136 6-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 137 N⁶-[(1S)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 138 N-hydroxy-7-methyl-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 139 N²-hydroxy-N⁶-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 140 6-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 141 5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 142 5-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 143 7-(2-fluorophenyl)-N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 144 N-hydroxy-6-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 145 N-hydroxy-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 146 N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 147 N⁶-[(1R)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 148 5-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2- carboxamide 149 6-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 150 5-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 151 N-hydroxy-5-[(4′-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 152 N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 153 N-hydroxy-3-methyl-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 154 N⁵-[(1R)-1-(4-chlorophenyl)ethyl]-N²-hydroxy-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 155 N⁶-(4-chlorobenzyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 156 N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 157 5-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 158 N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 159 6-[(5-amino-1H-pyrazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 160 6-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 161 5-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 162 N-hydroxy-7,7-dimethyl-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5- yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 163 N²-hydroxy-N⁶-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 164 6-[3-fluoro-5-(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 165 N-hydroxy-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 166 N-hydroxy-5-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 167 N-hydroxy-6-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 168 5-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 169 N⁶-(4-butylphenyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 170 5-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2- carboxamide 171 N-hydroxy-6-[4-(trifluoromethyl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 172 N-hydroxy-5-(propylsulfonyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 173 tert-butyl 2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate 174 N-hydroxy-6-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 175 N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4-methyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 176 N²-hydroxy-N⁶-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide 177 6-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 178 6-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 179 N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 180 N-hydroxy-6-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrol-5-yl}carbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 181 N-hydroxy-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 182 6-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 183 6-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 184 6-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 185 N-hydroxy-6-{[4-(trifluoromethyl)phenyl]acetyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 186 6-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- carboxamide 187 N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 188 6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 189 N⁵-(2,6-difluorophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 190 5-(4-tert-butylbenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 191 N⁵-benzyl-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 192 5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 193 5-(4-chlorobenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 194 N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 195 5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 196 N⁵-(4-cyanophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 197 N-hydroxy-3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 198 5-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 199 N-hydroxy-3-methyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 200 N⁵-(3,4-dimethylphenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 201 N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 202 N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 203 5-[(3S,5S,7S)-1-adamantylcarbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 204 5-(2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 205 5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 206 N⁵-(2,3-dihydro-1-benzofuran-5-yl)-N²-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine- 2,5(4H)-dicarboxamide 207 5-(biphenyl-4-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 208 N-hydroxy-7,7-dimethyl-5-[(3-phenyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 209 N-hydroxy-5-(4-methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 210 N-hydroxy-7,7-dimethyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 211 N-hydroxy-7,7-dimethyl-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 212 tert-butyl 2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate 213 N²-hydroxy-7,7-dimethyl-N⁵-(2-phenylethyl)-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide 214 N-hydroxy-5-(4-methoxybenzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 215 5-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 216 5-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 217 N-hydroxy-3-methyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 218 5-(4-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 219 N-hydroxy-3-methyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 220 N-hydroxy-7,7-dimethyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 221 5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 222 N-hydroxy-7,7-dimethyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 223 5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 224 N-hydroxy-7,7-dimethyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 225 5-(4-tert-butylbenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 226 N-hydroxy-7,7-dimethyl-5-(2-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 227 N-hydroxy-7,7-dimethyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 228 N-hydroxy-7,7-dimethyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 229 5-butyryl-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 230 5-(1-adamantylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 231 5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide 232 N-hydroxy-3-methyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 233 5-(biphenyl-4-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 234 5-(2-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide 235 N-hydroxy-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 236 N⁵-[2-(dimethylamino)ethyl]-N²-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 237 N-hydroxy-3-methyl-5-[(4-methylpiperidin-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide 238 N-hydroxy-6-(piperidin-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide 239 N-hydroxy-5-[(2S)-3-methyl-2-(methylamino)butanoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxamide

4. General Synthetic Methods and Intermediates

The compounds of the present invention can be prepared by methods known to one of ordinary skill in the art and/or by reference to the schemes shown below and the synthetic examples that follow. Exemplary synthetic routes are set forth in Schemes below, and in the Examples.

One of ordinary skill in the art will appreciate that the transformations shown below in Schemes can also be carried out on analogous compounds containing one or more substituents on Ring A and at the R¹ position, or on analogous compounds with different Ring A ring sizes.

Scheme 1 shows a general route for preparing compounds of formula iii. As shown in Scheme 1, methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, is treated with a carboxylic acid, R³—CO₂H, using a coupling agent in the presence of a base (Method A). Suitable coupling agents include, but are not limited to, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). Suitable bases for Method A include, but are not limited to, triethylamine, N,N′-diisopropylethylamine and N-methylmorpholine. Suitable solvents for Method A include, but are not limited to, dichloromethane (DCM), tetrahydrofuran (THF), N,N′-dimethylformamide (DMF), N-methylpyrrolidone (NMP) or N,N′-dimethylacetamide. Conversion of ii to the corresponding hydroxamate iii is achieved by heating ii in the presence of hydroxylamine hydrochloride and potassium hydroxide in an appropriate solvent such as methanol (Method B). Conversion to the corresponding hydroxamate can also be achieved using the potassium salt of hydroxylamine (Huang et al., J. Med. Chem. 2009, 52(21):675).

Scheme 2 shows a general route for preparing compounds of formula vi. Amides of formula iv, where v is 1-2, are prepared by Method A, using either chloroacetic acid or 3-chloropropionic acid, and are then reacted with oxygen (R³—OH) or nitrogen nucleophiles (R³—NH₂) in a solvent such as CH₂Cl₂ or DMF, in the presence of a base, such as N,N′-diisopropylethylamine (Method C; see Takikawa et al., Organic Lett. 2007, 9(14):2713-2716; Slee et al., J. Med. Chem. 2008, 51(6):1730-1739) to give compounds of formula vi where X is —O— or —NH—. Subsequent conversion of compounds of formula v to the corresponding hydroxamates vi is carried out as described in Scheme 1 using Method B.

Scheme 3 shows a general route for preparing compounds of formula viii. As shown in Scheme 3, methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated with the appropriate sulfonyl chloride, R³—SO₂Cl, and DMAP in DMF at ambient temperature (Method D). Method D may also be carried out in a solvent such as DCM or N,N′-dimethylacetamide. Subsequent conversion of the resulting compounds of formula vii to the corresponding hydroxamates viii is carried out as described in Scheme 1 using Method B.

Scheme 4 shows a general route for preparing compounds of formula xi. Sulfonamides of formula ix bearing a pendant aromatic bromide can be prepared as described in Scheme 3, and are then subjected to a Suzuki coupling with a boronic acid, R^(5d′)—B(OH)₂, in the presence of a Pd-catalyst such as Pd(PPh₃)₄, and a base such as Na₂CO₃ (see Weinstein et al., Bioorg. Med Chem. Lett. 2005 15(5): 1435-1440) to afford sulfonamides of formula x. Other Pd-mediated coupling conditions such as the reaction of an organo-stannane compound with an aromatic halide, or reaction with amines in a Buchwald-Hartiwig type coupling may be employed to generate compounds of formula x where R^(5d′) is for example an aromatic ring, a heteroaromatic ring or an amine containing moiety. Subsequent conversion of compounds of formula x to the corresponding hydroxamates of formula xi is carried out as described in Scheme 1 using Method B.

Scheme 5 shows a general route for preparing compounds of formula xiii. As shown in Scheme 5, methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated with an appropriate alkyl halide (R³—CH₂—Br or R³—CH₂—Cl), in the presence of a suitable base such as Et₃N in a solvent such as DMF (Method F) to afford compounds of formula xii. Alternatively, a reductive alkylation with an aldehyde in the presence of a reducing agent can be used to generate compounds of formula xii. Subsequent conversion of compounds of formula xii to the corresponding hydroxamate xiii is carried out as described in Scheme 1 (Method B).

Scheme 6 shows a general route for preparing compounds of formula xv. As shown in Scheme 6, a solution of methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, and optionally a base in a solvent is treated with an isocyanate (R³—NCO), at ambient or elevated temperature to afford compounds of formula xiv (Method G). Suitable bases for Method G include, but are not limited to triethylamine, N,N′-diisopropylethylamine and N-methylmorpholine. Suitable solvents for Method G include, but are not limited to, DCM, THF, DMF, NMP and N,N′-dimethylacetamide. Subsequent conversion of compounds of formula xiv to the corresponding hydroxamates of formula xv is carried out as described in Scheme 1 using Method B.

Scheme 7 shows a general route for preparing compounds of formula xviii As shown in Scheme 7, methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated with ammonium thiocyanate in a solvent such as THF at an elevated temperature (Method H). Cyclization of the resulting thiourea xvi to the aminothiazole xvii is accomplished upon treatment with an alpha-haloketone, (for example; R⁵—C(O)—CH₂Cl) in a solvent such as 1,4-dioxane at ambient or elevated temperature (Method I). Subsequent conversion of compounds of formula xvii to the corresponding hydroxamates of formula xviii is carried out as described in Scheme 1 using Method B.

Scheme 8 shows a general route for preparing compounds of formula xxvi and xxvii. Ring expansion of compound xix, (prepared as described by Padwa et. al., J. Org. Chem. 1989, 54(2): 299-308) via a Schmidt rearrangement (Method J) followed by reduction of the resulting amides with borane (Method K) affords amines xx and xxi (in a fashion analogous to that described in PCT Int. Appl. Pub. WO 08/076954). Subsequent protection of the amines with Boc-anhydride provides compounds xxii and xxiii (Method L). Bromination of xxii and xxiii followed by Pd-catalyzed carbonylation with carbon monoxide provides intermediates xxiv and xxv (Method M; as exemplified in Janetka et al., Bioorg. Med. Chem. Lett. 2008, 18(14): 4242-4248; and PCT Int. Appl. Pub. WO 05/037214). Subsequent removal of the Boc-protecting group (Method N) under acidic conditions yields compounds xxvi and xxvii. It will be appreciated that analogous transformations to those described in Scheme 1-7 above can be achieved starting from the compounds formula xxvi and xxvii.

Scheme 9 shows a general route for the preparation of compounds of formula xxxiii from commercially available halo-pyridines. Reaction of pyridine xxviii with LDA followed by quenching with DMF gives pyridine aldehyde xxix (Method O, see Ondi et al., Tetrahedron 2005, 61(3), 717-725). Palladium catalyzed reaction of xxix with Ar-boronic acids or Ar-boronates (where Ar is substituted or unsubstituted aryl or heteroaryl) affords compounds of formula XXX (Method P, see Fujihara et al., Organic Letters 2009, 11(10): 2121-2124; Rocca et al., J. Org. Chem. 1993, 58(27): 7831; and Rocca et al., Tetrahedron 1993, 49(1): 49). Treatment with methyl 2-mercaptoacetate affects cyclization to the compound of formula xxxi (Method Q; see PCT Int. Appl. Pub. WO 05/110410). The pyridine ring is reduced followed by de-methylation to yields compounds of formula xxxiii (Methods R, S). It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula xxxiii.

Scheme 10 shows the methods described in Scheme 9 above applied to generate substituted compounds of formulas xxxv and xxxvii starting from commercially available halo-pyridines xxxiv and xxxvi. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula xxxv and xxxvii.

Scheme 11 shows a general route for the preparation of compounds of formula xxxxii. Cyclocondensation of 1,5-dicarbonyl compounds of formula xxxviii with ammonia, followed by dehydrogenation gives compounds of formula xxxix (Method T, see Kim et al., Tetrahedron Lett. 2008, 49(41): 5863-5866). Nitration of the compound of formula xxxix affords the compound of formula xxxx (Method U, see Katritzky et al., Organic & Biomolecular Chemistry 2005, 3(3): 538-541). Reduction of the nitro group followed by conversion of the aniline intermediate to fluorine gives compounds of formula xxxxi (Method V, see Motoyama et al., Organic Letters 2009, 11(6): 1345-1348; Clark et al., Bioorg. Med. Chem. 2008, 16(6): 3163-3170). Conversion of the compound of formula xxxxi to compounds of formula xxxxii can be achieved with the methods described above (Methods O, Q, R, S). It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula xxxxii.

Scheme 12 above shows an extension of the chemistry described in Schemes 9 and 11 to generate compounds of formula xxxxv. Bromination of pyridine xxxx with NBS gives compounds of formula xxxxiii (Method W, see Carroll et al., J. Med. Chem. 2002, 45(21): 4755-4761). The pyridine of formula xxxxiii can be converted to compounds of formula xxxxiv by a palladium catalyzed coupling reaction in a similar manner as described in Scheme 9 (Method P). The conversion of the compounds of formula xxxxiv to xxxxv can be achieved as described above in Schemes 9 and 11 (Methods V, O, Q, R, S). It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula xxxxv.

Scheme 13 shows another general route for the preparation of the compound of formula xxxxviii. Condensation of ethylmercaptoacetate with commercially available compound xxxxvi in the presence of base (Method X, see Pessoa-Mahana et al. Heterocycles 2008, 75(8), 1913-1929; PCT Int. Appl. Pub. WO 05/110410) affords the compound of formula xxxxvii. Reduction of the pyridyl ring can be achieved using hydrogen over Adam's catalyst (Method Y, see Wang et al., J. Med. Chem. 2007, 50, 199-210) to give compounds of formula xxxxviii. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula xxxxviii.

Scheme 14 above shows a general route for the preparation of compounds of formula Lii. Protected piperidones xxxxix (where each R² may be the same or different; derived from commercial sources or accessed through literature routes) can be chloroformylated using a Vilsmer-Hack reaction to afford compounds of formula L (Method Z, see Grunewald et al., Bioorg. Med. Chem. 2008, 16(1), 542-559). Treatment with ethylmercaptoacetate in the presence of excess triethylamine provides compounds of formula Li (Method AA, see Venkatesan et al., J. Med. Chem. 2006, 45(15), 4623). Subsequent removal of the Boc-protecting group (Method N) under acidic conditions yields compounds of formula Lii. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compounds of formula Lii.

Scheme 15 above shows a general route for the preparation of the compound of formula Lv. Condensation of Liii (prepared as described by Tucker et al., J. Med. Chem. 2008, 51(20), 6503-6511) with ethylmercaptoacetate in the presence of a base affords the bicyclic compound of formula Liv (Method BB; see PCT Int. Appl. Pub. WO 05/077926). The pyridyl ring can then be reduced with hydrogen over Adam's catalyst (Method Y). It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compound of formula Lv.

Scheme 16 above shows a general route for the preparation of the compound of formula Lx. Protection of the secondary amine of compound xxxxviii can be achieved employing standard Boc anhydride in the presence of a suitable base (Method L; see Wang et al., J. Med. Chem. 2007, 50(2):199-210). Saponificiation of the ester of Lvi with sodium hydroxide (Method CC) provides the free acid of compound Lvii which assists in the ortho-metallation at C-3 with t-BuLi which, upon quenching with N-fluorobenzenesulfonimide, generates compound Lviii (Method DD, see Torrado et al., Bioorg. Med. Chem. 2004, 12(20): 5277-5295). Re-esterfication is accomplished with TMS-diazomethane (Method EE) followed by removal of the Boc protecting group under acidic conditions (Method N) to generate compound Lx. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compound of formula Lx.

Scheme 17 above shows a general route for the preparation of the compound of formula Lxiii. Starting from the compound of formula Lvii (prepared as described above in Scheme 16), the compound of formula Lxi can be achieved through the carboxylic acid assisted ortho-metallation of Lvii with sec-BuLi/TMEDA followed by quenching with N-chloro succinimide (Method DD, see Torrado et al., Bioorg. Med. Chem. 2004, 12(20): 5277-5295). Subsequent modification of the protecting groups is achieved though esterification with TMS-diazomethane (Method EE) followed by removal of the Boc group under acidic conditions (Method N) to provide the compound of formula Lxiii. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compound of formula Lxiii.

Scheme 18 above shows a general route for the preparation of the compound of formula Lxvii. Condensation of commercially available Lxiv with ethylmercaptoacetate, followed by subsequent cyclization under basic conditions provides the compound of formula Lxv (Method FF, see U.S. App. Pub. No. 2006/0003990; Donoso et al. Synthesis 1992, (6):526-8). Methylation of the free hydroxyl, accomplished upon treatment with diazo((trimethylsilyl))methane (Method GG, see U.S. App. Pub. No. 2006/0003990) followed by removal of the Boc protecting group under acidic conditions (Method N) affords the compound of formula Lxvii. It will be appreciated that analogous transformations to those described in Schemes 1-7 above can be achieved starting from the compound of formula Lxvii.

5. Uses, Formulation and Administration

As discussed above, the present invention provides compounds and pharmaceutical compositions that are useful as inhibitors of MAC enzymes, particularly HDAC6, and thus the present compounds are useful for treating proliferative, inflammatory, infectious, neurological or cardiovascular disorders.

In some embodiments, the invention provides the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a proliferative disorder. In some embodiments, the invention provides a pharmaceutical composition for the treatment of a proliferative disorder comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides the use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a proliferative disorder. In some embodiments, the invention provides the use of an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a proliferative disorder.

The compounds and pharmaceutical compositions of the invention are particularly useful for the treatment of cancer. As used herein, the term “cancer” refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term “cancer” includes, but is not limited to, solid tumors and bloodborne tumors. The term “cancer” encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term “cancer” further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors that can be treated with the disclosed inhibitors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma.

Non-limiting examples of hematologic malignancies that can be treated with the disclosed inhibitors include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, compounds of the invention are suitable for the treatment of breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myeloid leukemia or acute lymphoblastic leukemia.

In other embodiments, compounds of the invention are suitable for the treatment of inflammatory and cardiovascular disorders including, but not limited to, allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure.

Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of HDAC6.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

In yet another aspect, a method for treating a proliferative, inflammatory, infectious, neurological or cardiovascular disorder is provided comprising administering an effective amount of a compound, or a pharmaceutical composition to a subject in need thereof. In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutical composition is that amount effective for treating a proliferative, inflammatory, infectious, neurological or cardiovascular disorder, or is that amount effective for treating cancer. In other embodiments, an “effective amount” of a compound is an amount which inhibits binding of HDAC6, and thereby blocks the resulting signaling cascades that lead to the abnormal activity of growth factors, receptor tyrosine kinases, protein serine/threonine kinases, G protein coupled receptors and phospholipid kinases and phosphatases.

The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating the disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

In some embodiments, a compound of formula (I) or a pharmaceutical composition thereof is administered in conjunction with an anticancer agent. As used herein, the term “anticancer agent” refers to any agent that is administered to a subject with cancer for purposes of treating the cancer. Combination therapy includes administration of the therapeutic agents concurrently or sequentially. Alternatively, the therapeutic agents can be combined into one composition which is administered to the patient.

Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide, lenalidomide, and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including inhibitors of IκB kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication. In certain embodiments, a compound of the invention is administered in conjunction with a proteasome inhibitor.

Another aspect of the invention relates to inhibiting HDAC6, activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula (I), or a composition comprising said compound. The term “biological sample”, as used herein, generally includes in vivo, in vitro, and ex vivo materials, and also includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically acceptable carriers to treat disorders, symptoms and diseases where HDAC6 plays a role.

EXPERIMENTAL PROCEDURES Definitions

-   AcOH acetic acid -   ACN acetonitrile -   ATP adenosine triphosphate -   BOC tert-butoxycarbonyl -   DCE dichloroethane -   DCM dichloromethane -   DIPEA diisopropylethyl amine -   DMF N,N-dimethylformamide -   DMFDMA N,N-dimethylformamide dimethyl acetal -   DMAP N,N-dimethylaminopyridine -   DMSO dimethylsulfoxide -   DPPA diphenylphosphoryl azide -   DTT dithiothreitol -   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride -   EDTA ethylenediaminetetraacetic acid -   EtOAc ethyl acetate -   EtOH ethanol -   FA formic acid -   FBS fetal bovine serum -   h hours -   HATU N,N,N′,N′-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium     hexafluorophosphate -   HBTU o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   HEPES N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) -   HOBT 1-hydroxybenztriazole hydrate -   HRMS high resolution mass spectrum -   LAH lithium aluminum hydride -   LCMS liquid chromatography mass spectrum -   m/z mass to charge -   Me methyl -   MeOH methanol -   min minutes -   MS mass spectrum -   MTT methylthiazoletetrazolium -   MOM-Cl methyl chloromethyl ether -   MWI microwave irradiation -   NMM N-methyl morpholine -   PBS phosphate buffered saline -   PKA cAMP-dependent protein kinase -   rt room temperature -   TEA triethylamine -   TFFA trifluoroacetic anhydride -   THF tetrahydrofuran -   TMB 3,3′,5,5′-Tetramethylbenzidine -   WST     (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene     disulfonate sodium salt)

Analytical Methods

NMR

1H NMR Spectra were run on a 300 MHZ or 400 MHz Bruker NMR unless otherwise stated.

LCMS

LCMS spectra were run on a Phenominex Luna 5 μm C18 50×4.6 mm column on a Hewlett-Packard HP1100 using one of the following gradients unless otherwise stated

(1) Method Formic Acid (FA): Acetonitrile containing 0 to 100 percent 0.1% formic acid in water (2.5 ml/min for a 3 minute run). (2) Method Ammonium Acetate (AA): Acetonitrile containing 0 to 100 percent 10 mM ammonium acetate in water (2.5 ml/min for a 3 minute run).

HPLC

Reverse phase preparative purification were performed on either a Gilson HPLC or Agilent A2Prep LCMS system employing a Waters Sunfire C18 10 mm 19×150 mm column unless otherwise stated.

Example 1 Synthesis of methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

Step 1: Methyl thieno[2,3-c]pyridine-2-carboxylate

To a 50-mL round-bottom flask was added 3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and N,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. To this solution was added potassium carbonate (1.22 g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned to a clear yellow solution after stirring for 10 min. After 30 min at 0° C., the reaction was warmed to room temperature and stirred over the weekend by which time a solid precipitate was formed. Water was added provide a homogeneous solution, which was cooled to 0° C., the solid was collected via vacuum filtration, and washed with cold water until clear and colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; ¹H NMR (d₆-DMSO, 300 MHz) 59.37 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 8.26 (d, J=0.6 Hz, 1H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1H), 3.92 (s, 3H).

Step 2: Methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

A solution of methyl thieno[2,3-c]pyridine-2-carboxylate (370 mg, 1.9 mmol) and acetonitrile (7.3 mL) was stirred at 42° C. for 6 h over which time the formation of a precipitate was observed. Upon cooling to room temperature, the solvent was removed in vacuo. To the material thus obtained was added methanol (10 mL) and platinum dioxide (100 mg, 0.4 mmol). The mixture was stirred under a balloon H₂ atmosphere pressure for 4 h. The solvent was then removed under reduced pressure and the residue obtained was partitioned between EtOAc and saturated aqueous NaHCO₃. Upon separation, the aqueous layer was extracted with EtOAc three additional times. The combined organic phases were further washed with saturated aqueous NaHCO₃, water and brine, dried over anhydrous MgSO₄ and concentrated to give methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.4 g, 95%) as an off-white solid. LCMS: (FA) ES+ 212; ¹H NMR (CDCl₃, 300 MHz) δ7.50 (s, 1H), 3.85 (s, 3H), 3.64 (m, 2H), 2.73 (m, 4H), 2.48 (s, 3H).

Step 3: Methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate

Into a 1000-mL round-bottom flask containing methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2-carboxylate (9.84 g, 46.6 mmol), and 1,4-dioxane (466 mL) was added N,N-diisopropylethylamine (81.1 mL, 466 mmol). The solution was cooled to 0° C. whereupon α-chloroethyl chloroformate (50.2 mL, 466 mmol) was added dropwise. Upon complete addition, the solution was warmed to room temperature and stirred for 3 h. The solvent was removed in vacuo and the residue obtained was dissolved in methanol (466 mL). The clear yellow solution heated to reflux for 3 h. Removal of the solvent under reduced pressure afforded a solid which was partitioned between dichloromethane and saturated aqueous NaHCO₃. The aqueous layer was further extracted with dichloromethane three times. The combined organic phases were washed with brine, dried over anhydrous MgSO₄ and concentrated. Purification via flash chromatography (50% EtOAc-hexanes to 1% triethylamine-99% EtOAc to 1% MeOH-1% triethylamine-98% EtOAc) afforded methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (5.08 g, 55%) as a brown solid. LCMS: (FA) ES+ 198; ¹H NMR (CDCl₃, 300 MHz) δ7.50 (s, 1H), 4.04 (s, 2H), 3.86 (s, 3H), 3.12 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H).

Example 2 Synthesis of 6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2 carboxamide (Compound 1)

To a solution of HBTU (38.4 mg, 0.101 mmol) and trimethylacetic acid (10.4 mg, 0.101 mmol) in DCM (2 mL) was then added triethylamine (28.3 μL, 0.203 mmol). The reaction solution was stirred at room temperature for 30 min. A solution of methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (20 mg, 0.101 mmol) in DCM was added in one portion. The solution was then stirred at room temperature overnight then further heated at 36° C. for 1 h. Upon cooling to room temperature, the reaction was diluted with DCM and washed with saturated aqueous NaHCO₃. The aqueous layer was extracted with methylene chloride twice, the combined organic phases were additionally washed with water, brine, dried over anhydrous MgSO₄ and concentrated to afford an oil residue. To the material obtained was added methanol (1 mL), hydroxylamine hydrochloride (28.2 mg, 0.406 mmol), and potassium hydroxide (45.5 mg, 0.811 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature and the solvent removed in vacuo. To the solid residue obtained was dissolved in DMSO (1.4 mL) and purified with Gilson prep-HPLC [202 nm, rt=5.13 (12 min), 15-45% MeCN—H₂O] to afforded 6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2 carboxamide (3.51 mg, 12%) as a white solid. LCMS: (FA) ES+ 283; ¹H NMR (CDCl₃, 400 MHz) δ8.13 (s, 1H), 6.91 (s, 1H), 4.44 (s, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.37 (t, J=5.9 Hz, 2H), 0.92 (s, 9H).

Example 3 Synthesis of 6-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2 carboxamide (Compound 2)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 36.2%; Purification with Gilson prep-HPLC [198 nm, rt=5.64 (12 min), 20-50% MeCN—H₂O]. LCMS: (FA) ES+ 309; ¹H NMR (MeOD, 300 MHz) 87.30 (s, 1H), 4.75 (s, 2H), 3.83 (t, J=6.0 Hz, 2H), 2.65 (m, 3H), 1.74 (m, 6H), 1.41 (m, 4H).

Example 4 Synthesis of N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 3)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 22.9%; Purification with Gilson prep-HPLC [204 nm, rt=6.69 (12 min), 25-50% MeCN—H₂O]. LCMS: (FA) ES+ 323; ¹H NMR (d₆-DMSO, 400 MHz) 89.08 (s, 1H), 7.31 (s, 1H), 4.73 (s, 2H), 3.78 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 1.96 (m, 2H), 1.45 (m, 2H), 1.33 (m, 6H).

Example 5 Synthesis of 6-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 4)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 35.9%; Purification with Gilson prep-HPLC [202 nm, rt=6.68 (12 min), 25-55% MeCN—H₂O]; LCMS: (FA) ES+ 379.

Example 6 Synthesis of N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2 carboxamide (Compound 5)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 12%; Purification with Gilson prep-HPLC [212 nm, rt=4.73 (12 min), 15-40% MeCN—H₂O]; LCMS: (FA) ES+ 309; ¹H NMR (d₆-DMSO, 400 MHz) 88.72 (s, 1H), 7.50 (q, J=1.0 Hz, 1H), 7.26 (q, J=2.0 Hz, 1H), 6.97 (s, 1H), 6.87 (d, J=5.2 Hz, 1H), 4.40 (s, 2H), 3.31 (m, 2H), 2.35 (m, 2H).

Example 7 Synthesis of N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 6)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 12%; LCMS: (FA) ES+ 361.

Example 8 Synthesis of 6-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 7)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 1.9%; LCMS: (FA) ES+ 373.

Example 9 Synthesis of N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 8)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.

Example 10 Synthesis of 6-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 9)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5%; LCMS: (FA) ES+ 421.

Example 11 Synthesis of 6-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 10)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.

Example 12 Synthesis of N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 11)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 6.2%; LCMS: (FA) ES+ 405.

Example 13 Synthesis of 6-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 12)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 3.3%; LCMS: (FA) ES+ 361.

Example 14 Synthesis of 6-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 13)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 2.4%; LCMS: (FA) ES+ 423.

Example 15 Synthesis of 6-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 14)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 1.8%; LCMS: (FA) ES+ 361.

Example 16 Synthesis of N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 15)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 3.1%; LCMS: (FA) ES+ 436.

Example 17 Synthesis of N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 16)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 9.8%; LCMS: (FA) ES+ 454.

Example 18 Synthesis of 6-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 17)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.6%; LCMS: (FA) ES+ 405.

Example 19 Synthesis of 6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 18)

A solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (40 mg, 0.203 mmol), 2,2-diphenylethanesulfonylchloride (114 mg, 0.406 mmol), N,N-dimethylaminopyridine (2.48 mg, 0.02 mmol), and triethylamine (56.5 uL, 0.406 mmol) in 1,2-dichloroethane (0.5 mL) was stirred at room temperature overnight. The reaction was diluted with dichloroethane and the solution was washed with saturated aqueous NaHCO₃. The aqueous layer was extracted with twice with dichloroethane, the combined organic phases were washed with brine, dried over anhydrous MgSO₄ and concentrated to give a solid residue.

To the solid obtained was added hydroxylamine hydrochloride (56.4 mg, 0.811 mmol), potassium hydroxide (91 mg, 1.62 mmol), and methanol (2 mL, 49 mmol). The mixture was heated at 80° C. for 3 h, cooled to room temperature and the solvent removed under reduced pressure. To the residue was dissolved in DMSO (1.5 mL) purified via Gilson prep-HPLC [208 nm, rt=7.30 (12 min), 30-60% MeCN—H₂O] to afford 32.3 mg (32.4%) 6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2 carboxamide as a white solid. LCMS: (FA) ES+ 443; ¹H NMR (MeOD, 400 MHz) δ 7.35-7.12 (m, 11H), 4.51 (t, J=7.0 Hz, 1H), 4.20 (s, 2H), 3.96 (d, J=7.2 Hz, 2H), 3.28 (d, J=5.2 Hz, 2H), 2.59 (d, J=6.0 Hz, 2H).

Example 20 Synthesis of 6-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2 carboxamide (Compound 19)

The title compound was prepared in an analogous fashion to that described in Example 19 Yield: 5.4%; Purification with Gilson prep-HPLC [282 nm, rt=5.74 (12 min), 20-50% MeCN—H₂O]; LCMS: (FA) ES+ 319; ¹H NMR (MeOD, 400 MHz) δ 8.10 (s, 1H), 6.92 (s, 1H), 4.17 (s, 2H), 3.22 (t, J=6.0 Hz, 2H), 2.69 (t, J=7.8 Hz, 2H), 2.42 (t, J=5.8 Hz, 2H), 1.35 (m, 2H), 1.07 (m, 2H), 0.55 (t, J=7.4 Hz, 3H).

Example 21 Synthesis of 6-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 20)

The title compound was prepared in an analogous fashion to that described in Example 19. Yield: 5.6%; Purification with Gilson prep-HPLC [196 nm, rt=5.71 (12 min), 20-45% MeCN—H₂O]; LCMS: (FA) ES+ 358; ¹H NMR (MeOD, 400 MHz) δ 8.47 (s, 1H), 7.26 (s, 1H), 4.51 (s, 2H), 3.57 (t, J=6.0 Hz, 2H), 2.69 (q, J=7.3 Hz, 2H), 2.65 (s, 3H), 2.36 (s, 3H).

Example 22 Synthesis of N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 21)

The title compound was prepared in an analogous fashion to that described in Example 19. Yield: 53.2%; Purification with Gilson prep-HPLC [232 nm, rt=7.41 (12 min), 30-65% MeCN—H₂O]. LCMS: (FA) ES+ 407; ¹H NMR (MeOD, 400 MHz) δ 8.04 (d, J=8.0 Hz, 2H), 7.98 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 4.40 (s, 2H), 3.42 (t, J=6.0 Hz, 2H), 2.65 (t, J=6.0 Hz, 2H).

Example 23 Synthesis of 6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 22)

A solution of 7-(chloromethyl)-3,4-dihydro-2H-1,5-benzodioxepine (0.06 g, 0.3 mmol) and methyl thieno[2,3-c]pyridine-2-carboxylate (0.046 g, 0.24 mmol) in acetonitrile (2 mL) was heated at 40° C. overnight then at 60° C. for 4 h. Upon cooling to room temperature, the solvent was removed under reduced pressure to afford a solid residue. The material thus obtained was dissolved in methanol (2 mL, 49 mmol), was cooled to −78° C. under an N₂ atmosphere and sodium borohydride (54.5 mg, 1.44 mmol) was added slowly in portions. Upon complete addition, the reaction mixture was allowed to warm to room temperature. The solvent was removed under reduced pressure and the residue obtained was partitioned between dichloroethane and water. The aqueous layer was extracted with dichloroethane (2×), the combined organic phases were dried over anhydrous MgSO₄, and concentrated to give an oil.

To the material obtained was added potassium hydroxide (108 mg, 1.92 mmol), hydroxylamine hydrochloride (66.7 mg, 0.96 mmol) and methanol (2 mL, 49 mmol). The reaction mixture was heated at 80° C. for 3 h. Upon cooling to room temperature, the solvent was removed under reduced pressure and the residue obtained was dissolved in DMSO (1.5 mL) and purified via Gilson prep-HPLC [274 nm, rt=3.25 (12 min), 2-25% MeCN—H₂O] to give 17.9 mg (20.7%) 6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydro thieno[2,3-c]pyridine-2-carboxamide as a white solid. LCMS: (FA) ES+ 361; ¹H NMR (d₆-DMSO, 400 MHz) δ 8.21 (s, 1H), 7.31 (s, 1H), 6.91 (m, 3H), 4.10 (m, 4H), 3.56 (s, 4H), 2.67 (m, 2H), 2.61 (m, 2H), 2.07 (m, 2H).

Example 24 Synthesis of N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 23)

The title compound was prepared in an analogous fashion to that described in Example 23. Yield: 2.6%; Purification with Gilson prep-HPLC [260 nm, rt=3.26 (12 min), 2-25% MeCN—H₂O]; LCMS: (FA) ES+ 355; ¹H NMR (MeOD, 400 MHz) δ 8.36 (s, 1H), 8.22 (m, 1H), 7.72 (m, 3H), 7.52 (m, 2H), 7.28 (s, 1H), 6.52 (m, 1H), 3.83 (s, 2H), 3.75 (s, 2H), 2.88 (t, J=5.8 Hz, 2H), 2.77 (t, J=5.8 Hz, 2H).

Example 25 Synthesis of N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7 tetrahydro thieno[2,3-c]pyridine-2-carboxamide (Compound 24)

The title compound was prepared in an analogous fashion to that described in Example 23. Yield: 9.5%; Purification with Gilson prep-HPLC [272 nm, rt=4.03 (12 min), 10-30% MeCN—H₂O]; LCMS: (FA) ES+ 370; ¹H NMR (MeOD, 400 MHz) δ 8.22 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.48 (m, 1H), 7.32 (tt, J=7.6, 1.2 Hz, 2H), 3.92 (s, 2H), 3.84 (s, 2H), 2.95 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.8 Hz, 2H), 2.40 (s, 3H).

Example 26 Synthesis of 6-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2-carboxamide (Compound 25)

The title compound was prepared in an analogous fashion to that described in Example 23. Yield: 5.6%; Purification with Gilson prep-HPLC [306 nm, rt=3.02 (12 min), 2-22% MeCN—H₂O]; LCMS: (FA) ES+ 347; ¹H NMR (MeOD, 400 MHz) δ 8.32 (s, 1H), 7.97 (m, 1H), 7.70 (m, 2H), 7.28 (s, 1H), 4.35 (s, 2H), 3.86 (s, 2H), 2.98 (t, J=5.8 Hz, 2H), 2.78 (t, J=5.8 Hz, 2H).

Example 27 Synthesis of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Into a 100-mL round-bottom flask charged with 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1 g, 3.21 mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) and DCM (16 mL) was slowly added trifluoroacetic acid (1.48 mL, 19.3 mmol) at 0° C. The solution was then stirred at room temperature for 60 min. To the reaction mixture was then added saturated aqueous NaHCO₃ solution (10 mL) and DCM (10 mL). Upon separation of the layers, the aqueous solution was further extracted with DCM (20 mL) twice. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated to give ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.547 g, 81%) as an oil. LCMS: (FA) ES+ 212.

Example 28 Synthesis of 5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 26)

To a solution of HATU (104 mg, 0.274 mmol) and trimethylacetic acid (28 mg, 0.274 mmol) in DCM (2 mL) was added triethylamine (104 μL, 0.203 mmol). The reaction solution was stirred at room temperature for 30 min. A solution of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20 mg, 0.101 mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) in DMF (0.5 mL) was added in one portion. The solution was then stirred at room temperature overnight. The solution was then diluted with DCM and washed with saturated aqueous NaHCO₃. The aqueous layer was extracted with DCM twice, the combined organic phases were additionally washed with water, brine, dried over anhydrous MgSO₄ and concentrated to afford an oil residue. To the material thus obtained was added methanol (2 mL), hydroxylamine hydrochloride (52.1 mg, 0.75 mmol), and potassium hydroxide (84.2 mg, 1.5 mmol). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and the solvent removed in vacuo. The solid residue obtained was dissolved in DMSO (1.4 mL) and purified with Gilson prep-HPLC [282 nm, rt=5.2 (12 min), 15-40% MeCN—H₂O] to afforded white solid (16.1 mg, 24%) as a white solid. LCMS: (FA) ES+ 283; ¹H NMR (d₆,DMSO, 400 MHz) δ 11.13 (s, 1H), 9.08 (s, 1H), 7.37 (s, 1H), 4.56 (s, 2H), 3.83 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.4 Hz, 2H), 1.22 (s, 9H).

Example 29 Synthesis of N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 27)

The title compound was prepared in an analogous fashion to that described in Example 28. (18.3 mg, 24%). LCMS: (FA) ES+ 306.

Example 30 Synthesis of N-hydroxy-5-(1-methylcyclohexanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 28)

The title compound was prepared in an analogous fashion to that described in Example 28. (21.0 mg, 26%). LCMS: (FA) ES+ 323.

Example 31 Synthesis of N-hydroxy-5-(5-methylpyrazine-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 29)

The title compound was prepared in an analogous fashion to that described in Example 28. (10.3 mg, 12.9%). LCMS: (FA) ES+ 319.

Example 32 Synthesis of N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 30)

The title compound was prepared in an analogous fashion to that described in Example 28. (14.9 mg, 16.9%). LCMS: (FA) ES+ 354.

Example 33 Synthesis of 5-(cyclohexanecarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 31)

The title compound was prepared in an analogous fashion to that described in Example 28. (14.5 mg, 18.8%). LCMS: (FA) ES+ 309.

Example 34 Synthesis of 5-(4-(4,6-dimethoxypyrimidin-2-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 32)

The title compound was prepared in an analogous fashion to that described in Example 28. (18.7 mg, 20.6%). LCMS: (FA) ES+ 309.

Example 35 Synthesis of 5-(adamantan-1-ylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 33)

The title compound was prepared in an analogous fashion to that described in Example 28. (26.7, 41.1%); LCMS: (FA) ES+ 361.

Example 36 Synthesis of N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 34)

The title compound was prepared in an analogous fashion to that described in Example 28. Yield: 49.9%; Purification with Gilson prep-HPLC [228 nm, rt=7.39 (12 min), 30-65% MeCN—H₂O]. LCMS: (FA) ES+ 407; ¹H NMR (MeOD, 400 MHz) δ 8.04 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 4.26 (s, 2H), 3.51 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H).

Example 37 Synthesis of 6-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 184)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 10.5%; LCMS: (FA) ES+ 402.

Example 38 Synthesis of N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 68)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 4.2%; LCMS: (FA) ES+ 385.

Example 39 Synthesis of 6-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 47)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 11.9%; LCMS: (FA) ES+ 352.

Example 40 Synthesis of N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 81)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 11.8%; LCMS: (FA) ES+ 320.

Example 41 Synthesis of N-hydroxy-6-(2-(2-methylthiazol-4-yl)acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 75)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.4%; LCMS: (FA) ES+ 338.

Example 42 Synthesis of 6-(furan-2-carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 42)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 17.7%; LCMS: (FA) ES+ 293.

Example 43 Synthesis of 6-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 178)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 22.9%; LCMS: (FA) ES+ 321.

Example 44 Synthesis of 6-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 56)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.0%; LCMS: (FA) ES+ 398.

Example 45 Synthesis of M-[2-fluoro-5-(trifluoromethyl)phenyl]-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 106)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5.2%; LCMS: (FA) ES+ 389.

Example 46 Synthesis of N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 179)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.1%; LCMS: (FA) ES+ 354.

Example 47 Synthesis of N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 65)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 398.

Example 48 Synthesis of 6-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 140)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 339.

Example 49 Synthesis of N-hydroxy-6-(2-methyl-4-phenylpyrimidine-5-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 48)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 16.8%; LCMS: (FA) ES+ 395.

Example 50 Synthesis of N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 156)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 375.

Example 51 Synthesis of 6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 100)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 365.

Example 53 Synthesis of 6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 118)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 12.7%; LCMS: (FA) ES+ 373.

Example 54 Synthesis of 6-(2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 125)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 335.

Example 55 Synthesis of N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 98)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 14.6%; LCMS: (FA) ES+ 324.

Example 56 Synthesis of N-hydroxy-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 95)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 11.6%; LCMS: (FA) ES+ 354.

Example 57 Synthesis of N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 127)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 369.

Example 58 Synthesis of 6-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 149)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 22.4%; LCMS: (FA) ES+ 335.

Example 59 Synthesis of 6-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 177)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 21.3%; LCMS: (FA) ES+ 322.

Example 60 Synthesis of N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 107)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5.5%; LCMS: (FA) ES+ 384.

Example 61 Synthesis of N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 94)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 18.3%; LCMS: (FA) ES+ 307.

Example 62 Synthesis of 6-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 69)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 16.7%; LCMS: (FA) ES+ 363.

Example 63 Synthesis of 6-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 36)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 5.7%; LCMS: (FA) ES+ 439.

Example 64 Synthesis of 6-(2-(3,5-dimethylisoxazol-4-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 62)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 8.3%; LCMS: (FA) ES+ 336.

Example 65 Synthesis of N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 116)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 19.5%; LCMS: (FA) ES+ 306.

Example 66 Synthesis of 6-(2-(3,5-difluorophenyl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 52)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 4.6%; LCMS: (FA) ES+ 353.

Example 67 Synthesis of 6-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 51)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 20.1%; LCMS: (FA) ES+ 335.

Example 68 Synthesis of 6-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 88)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 24.5%; LCMS: (FA) ES+ 363.

Example 69 Synthesis of N-hydroxy-6-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 93)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 389.

Example 70 Synthesis of 6-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 64)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 20.9%; LCMS: (FA) ES+ 359.

Example 71 Synthesis of 6-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 67)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 20.2%; LCMS: (FA) ES+ 363.

Example 72 Synthesis of 6-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 131)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 8.0%; LCMS: (FA) ES+ 417.

Example 73 Synthesis of 6-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 186)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 335.

Example 74 Synthesis of 6-(3-(1H-pyrazol-1-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 133)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 7.2%; LCMS: (FA) ES+ 369.

Example 75 Synthesis of 6-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 182)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 19.3%; LCMS: (FA) ES+ 321.

Example 76 Synthesis of N-hydroxy-6-(4-(trifluoromethyl)benzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 171)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 8.4%; LCMS: (FA) ES+ 371.

Example 77 Synthesis of N-hydroxy-6-(quinoline-8-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 99)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 10.1%; LCMS: (FA) ES+ 354.

Example 78 Synthesis of N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 89)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 11.0%; LCMS: (FA) ES+ 417.

Example 79 Synthesis of N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 84)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 22.7%; LCMS: (FA) ES+ 383.

Example 80 Synthesis of N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 146)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 12.8%; LCMS: (FA) ES+ 310.

Example 81 Synthesis of N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 152)

The title compound was prepared in an analogous fashion to that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 395.

Example 82 Synthesis of N2-hydroxy-N6-(4-methylbenzyl)-4,5-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 103)

To a vial charged with 1-(isocyanatomethyl)-4-methylbenzene (0.032 g, 0.22 mmol) was added methyl 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.0434 g, 0.22 mmol) in 1,2-dichloroethane (2 mL). The solution was stirred at rt for 2 h. The solvent was evaporated. To the residue was added potassium hydroxide (0.099 g, 1.76 mmol), hydroxylamine hydrochloride (0.046 g 0.66 mmol), and methanol (2 mL). The vial was capped and heated at 80° C. with vigorous shaking for 1 h, then cooled to rt. To the vial was added acetic acid (0.1 mL) and the solution was shaken at rt for 15 min. The solvent was completed removed. To the residue was added DMSO (1.3 mL) and the solution was filtered and purified by Gilson prep-HPLC to afford 0.007 g (11.2%) of a white solid. LCMS: (FA) ES+346.

Example 83 Synthesis of N²-hydroxy-N⁶-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 132)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 20.4%; LCMS: (FA) ES+ 399.

Example 84 Synthesis of N²-hydroxy-N⁶-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 80)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 4.8%; LCMS: (FA) ES+ 332.

Example 85 Synthesis of N²-hydroxy-N⁶-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 54)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 3.6%; LCMS: (FA) ES+ 386.

Example 86 Synthesis of N⁶-(4-butylphenyl)-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 169)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 12.1%; LCMS: (FA) ES+ 374.

Example 87 Synthesis of N²-hydroxy-N⁶-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 40)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 6.8%; LCMS: (FA) ES+ 400.

Example 88 Synthesis of N²-hydroxy-N⁶-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 176)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 26.3%; LCMS: (FA) ES+ 360.

Example 89 Synthesis of N²-hydroxy-N⁶-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 139)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 5.2%; LCMS: (FA) ES+ 360.

Example 90 Synthesis of N⁶-cyclohexyl-N²-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 76)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 20.1%; LCMS: (FA) ES+ 324.

Example 91 Synthesis of N²-hydroxy-N⁶-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 163)

The title compound was prepared in an analogous fashion to that described in Example 82. Yield: 13.2%; LCMS: (FA) ES+ 444.

Example 92 Synthesis of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Step 1: ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate

To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol) and triethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at room temperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g, 0.042 mol). The reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature, the solvent was evaporated and the residue obtained partitioned between ethyl acetate and water. The organic layer was dried over anhydrous NaHSO₄, filtered and concentrated. The oily residue was passed through a pad of silica (ethyl acetate/hexane: 5/1) to afford ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g, 22%). LCMS (FA) ES+ 222; ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).

Step 2: ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A mixture of ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (4 g, 0.018 mol) and PtO₂ (0.5 g, 0.002 mol) in ethanol (100 mL) was stirred under an H₂ atmosphere (3 atmospheres) for 72 hours at room temperature. The PtO₂ was removed by filtration, the filtrate was concentrated under reduced pressure and the residue obtained was purified by silica gel chromatography (DCM/EtOH=10:1) to afford ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (1.6 g, 40%). ES+ 226; ¹H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 3.21 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.7 Hz, 2H), 2.55 (s, 1H), 2.34 (s, 3H), 1.26 (t, J=6.0 Hz, 3H).

Example 93 Synthesis of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

Step 1: 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde

A solution of anhydrous DMF (142 mL, 1.85 mol) in anhydrous DCM (670 mL) was cooled to 0° C. A solution of POCl₃ (121 mL, 1.3 mol) in anhydrous DCM (87 mL) was added dropwise. Upon complete addition, the solution was warmed to room temperature and further to reflux for 30 minutes. A solution of 1-benzyl-3,3-dimethylpiperidin-4-one (75 g, 0.35 mol) in anhydrous DCM (133 mL) was added all at once to the boiling solution and the mixture was further refluxed overnight. The reaction was cooled to room temperature and added dropwise to a biphasic mixture of 4.0 M aqueous sodium acetate (1000 mL) and DCM (300 mL). Upon separation of the layers, the organic layer was washed with water, dried over anhydrous Na₂SO₄ and concentrated to dryness to afford 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (75 g, 82% crude yield).

Step 2: ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

To a solution of 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (75 g, 0.28 mol) in DCM (1.2 L) was added ethyl 2-mercaptoacetate (67 g, 0.56 mol) and triethylamine (85 g, 0.84 mol) was added slowly at room temperature. Upon complete addition, the reaction mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction was quenched with the addition of water. The organic layer was washed with water, dried over anhydrous Na₂SO₄, concentrated and purified by silica gel chromatography (0-20% EtOAc/hexane) to afford the title compound (31.7 g, 27.5% over two steps).

Step 3: ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate hydrochloride

A solution of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (14.6 g, 0.044 mol) in anhydrous DCM was cooled to 0° C. whereupon K₂CO₃ (6.1 g, 0.044 mmol) and α-chloroethyl chloroformate (6.97 g, 0.049 mol) were added. Upon complete addition, the reaction was heated at reflux overnight. The reaction was cooled to room temperature and diluted with DCM, then washed with saturated aqueous NaHCO₃ and brine respectively. The organic layer was dried over anhydrous Na₂SO₄ and evaporated to afford an oily residue which was taken up in EtOH and refluxed for 2 hours. The solvent was evaporated to dryness and the residue was washed with ethyl acetate to afford the desired product (9.6 g, 79%). ¹H NMR (400 MHz, DMSO) δ 9.82 (s, 2H), 7.64 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.15 (s, 2H), 3.26 (s, 2H), 1.42 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).

Step 4: ethyl 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of ethyl 7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20.5 g, 0.074 mol) and DIPEA (42.8 g, 0.37 mol) in DCM (400 mL) was cooled to 0° C. 2-nitrobenzene-1-sulfonyl chloride (17.3 g, 0.078 mol) was then added and the reaction mixture was allowed to warm to room temperature overnight. The crude reaction solution was applied directly to a silica gel column and purified (10-20% EtOAc/hexane) to afford product (27.6 g, 88%). NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=4.8, 2.4 Hz, 1H), 7.64-7.68 (m, 2H), 7.57 (dd, J=4.4, 2.4 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.33 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.33 (s, 2H), 1.31 (s, 6H), 1.19 (t, J=7.2 Hz, 3H),

Step 5: 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid

To a solution of ethyl 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (32.6 g, 76.8 mmol) in THF (853 mL) was added 1.0 M aqueous LiOH (307 mL, 307 mmol) and the reaction mixture stirred overnight at room temperature. The solution was concentrated and the residue dissolved in water (100 mL) and neutralized with 1.0 M, aqueous HCl (307 mL). The resulting precipitate was collected via vacuum filtration to afford white solid (29 g, 95%). LCMS (FA) ES+ 397; ¹H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 8.08 (dd, J=7.6, 1.6 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.95-7.86 (m, 2H), 7.49 (s, 1H), 4.36 (s, 2H), 3.40 (s, 2H), 1.28 (s, 6H).

Step 6: 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A solution of 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (20 g, 50 mmol) was cooled to 0° C. DIPEA (32.3 g, 250 mmol) was added and the solution was stirred at 0° C. for 30 minutes. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.8 g, 50 mmol) and HATU (22.8 g, 60 mmol) were then added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with water, brine and dried over anhydrous Na₂SO₄, concentrated and purified by silica gel chromatography (20-50% EtOAc/hexane) to afford product (23.5 g, 94%). LCMS (FA) ES+ 496; ¹H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.10 (dd, J=7.7, 1.5 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.90 (dtd, J=17.6, 7.5, 1.4 Hz, 2H), 7.41 (s, 1H), 4.92 (s, 1H), 4.33 (s, 2H), 4.00 (s, 1H), 3.50 (d, J=11.1 Hz, 1H), 3.38 (s, 2H), 1.72 (d, J=22.2 Hz, 3H), 1.53 (s, 3H), 1.27 (s, 6H).

Step 7: 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

To a mixture of 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (15.4 g, 31 mmol) and cesium carbonate (20.2 g, 62 mmol) in acetonitrile (800 mL) was added a solution of thiophenol (6.85 g, 62 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue applied to silica gel chromatography (0-20% DCM/MeOH) to afford the title compound (8.2 g, 85%). LCMS (FA) ES+ 311; ¹H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 7.30 (s, 1H), 4.91 (s, 1H), 4.01 (dd, J=15.6, 8.0 Hz, 1H), 3.71 (s, 2H), 3.55-3.44 (m, 1H), 2.71 (s, 2H), 1.69 (s, 3H), 1.53 (s, 3H), 1.25 (s, 6H).

Example 94 Synthesis of N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 194)

Step 1: ethyl 3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg, 0.1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine (52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room temperature for 15 minutes. A solution of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (22.5 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and the reaction was further stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCM (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). Upon separation of the layers, the aqueous layer was extracted with additional DCM (2 mL) and the combined organic layers were concentrated to dryness.

Step 2: N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogenous. To the heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). The formation of a white precipitate was observed. After heating at 90° C. for 30 minutes, the mixture was cooled to room temperature and the solids allowed to settle. The resulting solution was assumed to have a 1.7 M concentration of hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (1 mL, 1.7 mmol) was added to a solution of ethyl 3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate obtained in the previous step dissolved in methanol (1 mL). After stirring for 30 minutes at room temperature, the reaction was quenched with the addition of formic acid (0.1 mL, 3 mmol). The reaction mixture was concentrated to dryness and the residue obtained redissolved in DMSO (1 mL) and purified by reverse phase Gilson prep-HPLC to afford the title compound as a white solid (7.2 mg, 22.5% over two steps). LCMS (FA) ES+ 320; ¹H NMR (400 MHz, DMSO) δ 6.93-6.92 (m, 1H), 6.44 (dd, J=3.8, 1.6 Hz, 1H), 6.06 (dd, J=3.7, 2.6 Hz, 1H), 4.55 (s, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.67 (s, 3H), 2.88 (d, J=2.8 Hz, 2H), 2.22 (s, 3H).

Example 95

The following compounds were prepared in a fashion analogous to that described in Example 94 starting from the intermediates which were prepared as described above and the corresponding carboxylic acids.

Compound Structure LC-MS (FA) 221

ES+ 407 219

ES+ 331 233

ES+ 393 204

ES+ 297 209

ES+ 347 225

ES+ 373 229

ES+ 283 217

ES+ 318 232

ES+ 337 216

ES+ 357 199

ES+ 415 197

ES+ 338 205

ES+ 373 203

ES+ 375 193

ES+ 351

Example 96 Synthesis of 5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 192)

Step 1: ethyl 5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

A solution of 3-chloro-1-benzothiophene-2-carboxylic acid (23.4 mg, 0.11 mmol), N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine (52.2 pt, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room temperature for 15 minutes. A solution of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and the reaction was further stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCM (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). Upon separation of the layers, the aqueous layer was extracted with additional DCM (2 mL) and the combined organic layers were concentrated to dryness to afford the title compound.

Step 2: 5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

To a solution of ethyl 5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate obtained in step 1 in THF (0.5 mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The reaction was stirred at room temperature for 2 hours whereupon it was concentrated to dryness. The residue obtained was redissolved in DMSO (1 mL) and purified on Gilson prep-HPLC to afford the title compound (6.7 mg, 16% over two steps). LCMS (FA) ES+ 421; ¹H NMR (400 MHz, DMSO) δ 8.16-8.11 (m, 1H), 7.89-7.83 (m, 1H), 7.63-7.55 (m, 2H), 7.46-7.12 (m, 1H), 4.64 (d, J=104.6 Hz, 2H), 3.88-3.49 (m, 2H), 1.36 (br s, 3H), 1.20 (br s, 3H).

Example 97

The following compounds were prepared in a fashion analogous to that described in Example 96 starting from the intermediates which were prepared as described above and the corresponding carboxylic acids.

Compound Structure LC-MS (FA) 211

ES+ 414 226

ES+ 337 220

ES+ 332 215

ES+ 371 207

ES+ 407 208

ES+ 446 214

ES+ 361 234

ES+ 365 210

ES+ 334 222

ES+ 352 218

ES+ 365 198

ES+ 403 228

ES+ 429 224

ES+ 351 195

ES+ 387 227

ES+ 445 190

ES+ 387

Example 98 Synthesis of N²-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxamide (Compound 201)

A solution of 7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) and triethylamine (41.8 μL, 0.3 mmol) in 1,2-dichloroethane (1 mL) was added (S)-1-phenylethyl isocyanate (22.1 mg, 0.15 mmol). The reaction was stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was redissolved in tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in 1,4-dioxane (1 mL, 4 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100 LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS (FA) ES+ 374; ¹H NMR (400 MHz, MeOD) δ 7.35-7.24 (m, 5H), 7.20-7.15 (m, 1H), 5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 3.50 (d, J=4.6 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.30 (s, 6H).

Example 99

The following compounds were prepared in a fashion analogous to that described in Example 98 starting from the intermediates which were prepared as described above and the corresponding isocyanates.

Compound Structure LC-MS (FA) 213

ES+ 374 196

ES+ 371 189

ES+ 382 200

ES+ 374 206

ES+ 387 202

ES+ 374 191

ES+ 360

Example 100 Synthesis of tert-butyl 2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (Compound 212)

A mixture of 5-tert-butyl 2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g, 0.18 mmol; prepared as described in J. Med. Chem. 2006, 49(15): 4623), hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and potassium hydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was heated at 75° C. for 1 hour. Upon cooling to room temperature the reaction was quenched by the addition of acetic acid (100 μL, 1.8 mmol) and the solvent was evaporated to dryness. The residue was dissolved in DMSO (1 mL) and purified using a Gilson prep to afford a white solid (26.9 mg, 50%). LCMS (FA) ES+ 299; ¹H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 4.46 (s, 2H), 3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48 (s, 9H).

Example 101 Synthesis of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

Step 1: methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate

A solution of methyl thiophene-2-carboxylate (1 mL, 8.65 mmol) in chloromethyl methyl ether (1 mL, 13 mmol) was added dropwise to a suspension of zinc chloride (1.179 g, 8.65 mmol) in chloromethyl methyl ether (8 mL, 104 mmol) under an N₂ atmosphere. After complete addition, the mixture was stirred at room temperature for 15 minutes over which time the suspension became a homogenous clear colorless solution. The reaction was further warmed to 60° C. for 3 hours. The reaction mixture was cooled to room temperature and poured over ice. The mixture was stirred for 1 hour then extracted with EtOAc (30 mL). The organic layer was dried over anhydrous MgSO₄, concentrated and purified via silica chromatography (5-10% EtOAc/hexane) to afford a colorless solid (1.272 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 1H), 4.78 (s, 2H), 4.59 (s, 2H), 3.89 (s, 3H).

Step 2: methyl 5-[(2-nitrophenyl)sulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a solution of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate (4.106 g, 17.17 mmol) and 2-nitrobenzenesulfonamide (3.825 g, 18.92 mmol) in acetone (40 mL) was added 2.5 M of potassium carbonate in water (20 mL, 50 mmol). The resulting biphasic mixture was stirred at room temperature for 1 hour then further heated at 45° C. overnight resulting in formation of precipitate. The reaction mixture was cooled to room temperature and the precipitate was collected by vacuum filtration. The solid obtained was washed with water followed by cold methanol and dried under vacuum to afford an off white solid (3.352 g, 53%). LCMS (FA) ES+ 369; ¹H NMR (400 MHz, DMSO) δ 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90 (td, J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H), 4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).

Step 3: methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a mixture of methyl 5-[(2-nitrophenyl)sulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (3.297 g, 8.95 mmol) and cesium carbonate (5.6 g, 17 mmol) in acetonitrile (95 mL) was added a solution of benzenethiol (1.8 mL, 17 mmol) in acetonitrile (20 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was washed exhaustively with Et₂O to afford an off white solid (1.326 g, 80%). LCMS (FA) ES+ 184; ¹H NMR (400 MHz, MeOD) δ 7.59 (s, 1H), 4.32 (t, J=2.0 Hz, 2H), 4.17 (t, J=2.0 Hz, 2H), 3.85 (s, 3H).

Example 102 Synthesis of 5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide (Compound 223)

Step 1: methyl 5-pivaloyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride (0.92 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) respectively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with additional DCM (2 mL) and washed with saturated aqueous NaHCO₃ (2 mL). The aqueous layer was extracted with additional DCM (3 mL), and the combined organic layers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.

Step 2: 5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxamide

The residue obtained in the previous step was taken up in methanol (1.7 mL, 43 mmol) and to the solution was added hydroxylamine hydrochloride (0.035 g, 0.51 mmol) and potassium hydroxide (0.086 g, 1.5 mmol). The mixture was heated at 80° C. for 45 minutes. The reaction was cooled to room temperature and the solvent evaporated to dryness. The material was dissolved in DMSO (1 mL), the insolubles removed via filtration and purified by Gilson prep-HPLC. Lyophilization of fractions containing the desired product afforded the title compound as a white solid (6.1 mg, 33% over two steps). LCMS (FA) ES+ 267; ¹H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 9.14 (s, 1H), 7.43 (s, 1H), 4.74 (dd, J=137.5, 64.7 Hz, 4H), 1.22 (s, 9H).

Example 103

The following compounds were prepared in a fashion analogous to Example 102 starting from the intermediates which were prepared as described above and the corresponding carboxylic acids.

Com- LC-MS pound Structure (FA) 230

ES+ 347 231

ES+ 345

Example 104

The following compound was prepared in a fashion analogous to that described in Example 99 starting from the intermediate prepared as described in Example 2 employing the corresponding carboxylic acid.

Com- LC-MS pound Structure (FA) 159

ES+ 308

Example 105 Synthesis of 5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 240)

Step 1: ethyl 5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

To ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.237 g, 1.12 mmol), 4-chlorobenzoic acid (0.228 g, 1.46 mmol) in N,N-dimethylformamide (6 mL) was added a solution of fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.444 g, 1.68 mmol) in N,N-diisopropylethylamine (0.6 mL). The reaction solution was then stirred overnight at room temperature. Water was then added and the mixture was extracted into ethyl acetate. The organic layer was washed with brine and evaporated. Purification of the residue obtained on silica gel (0-10% ethyl acetate/DCM) afforded a sticky white solid (208 mg, 53%). LCMS (FA) ES+ 350.

Step 2: 5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogenous. To the heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). The formation of a white precipitate was observed. After heating at 90° C. for 30 minutes, the mixture was cooled to room temperature and the solids allowed to settle. The resulting solution was assumed to have a 1.7 M concentration of hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (3.5 mL 5.92 mmol) was added to a solution of ethyl 5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate obtained in the previous step dissolved in methanol (3.5 mL). After stirring for 30 minutes at room temperature, the reaction was quenched with the addition of acetic acid (0.3 mL, 5.86 mmol). The reaction mixture was concentrated to dryness and purified on a BioCAD 700E HPLC instrument using Sunfire C-18 (18×150 mm) column to afford a white solid (115 mg, 58%). LCMS (FA) ES+ 337; ¹H NMR (400 MHz, MeOD) δ 7.55-7.41 (m, 4H), 7.36 (br s, 0.5H), 7.13 (br s, 0.5H), 4.75 (br s, 1H), 4.52 (br s, 1H), 4.05 (br s, 1H), 3.70 (br s, 1H), 2.95 (br s, 2H).

Example 106 HDAC6 Enzyme Assay

To measure the inhibition of HDAC6 activity, purified human HDAC6 (BPS Bioscience; Cat. No. 5006) is incubated with substrate Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No. 1-1925) for 1 hour at 30° C. in the presence of test compounds or vehicle DMSO control. The reaction is stopped with the HDAC inhibitor trichostatin A (Sigma; Cat. No. T8552) and the amount of Arg-Gly-Lys-AMC generated is quantitated by digestion with trypsin (Sigma; Cat. No. T1426) and subsequent measurement of the amount of AMC released using a fluorescent plate reader (Pherastar; BMG Technologies) set at Ex 340 nm and Em 460 nm. Concentration response curves are generated by calculating the fluorescence increase in test compound-treated samples relative to DMSO-treated controls, and enzyme inhibition (IC₅₀) values are determined from those curves.

Example 107 Nuclear Extract HDAC Assay

As a screen against Class I HDAC enzymes, HeLa nuclear extract (BIOMOL; Cat. No. KI-140) is incubated with Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No. 1-1925) in the presence of test compounds or vehicle DMSO control. The Hela nuclear extract is enriched for Class I enzymes HDAC1, -2 and -3. The reaction is stopped with the HDAC inhibitor Trichostatin A (Sigma; Cat. No. T8552) and the amount of Arg-Gly-Lys-AMC generated is quantitated by digestion with trypsin (Sigma; Cat. No. T1426) and subsequent measurement of the amount of AMC released using a fluorescent plate reader (Pherastar; BMG Technologies) set at Ex 340 nm and Em 460 nm. Concentration response curves are generated by calculating the fluorescence increase in test compound-treated samples relative to DMSO-treated controls, and enzyme inhibition (IC₅₀) values are determined from those curves.

Example 108 Western Blot and Immunofluorescence Assays

Cellular potency and selectivity of compounds are determined using a published assay (Haggarty et al., Proc. Natl. Acad. Sci. USA 2003, 100 (8): 4389-4394) using Hela cells (ATCC cat# CCL-2™) which are maintained in MEM medium (Invitrogen) supplemented with 10% FBS; or multiple myeloma cells RPMI-8226 (ATCC cat# CCL-155™) which are maintained in RPMI 1640 medium (Invitrogen) supplemented with 10% FBS. Briefly, cells are treated with inhibitors for 6 or 24 h and either lysed for Western blotting, or fixed for immunofluorescence analyses. HDAC6 potency is determined by measuring K40 hyperacetylation of alpha-tubulin with an acetylation selective monoclonal antibody (Sigma cat# T7451) in IC50 experiments. Selectivity against Class I HDAC activity is determined similarly using an antibody that recognizes hyperacetylation of histone H4 (Upstate cat#06-866) in the Western blotting assay or nuclear acetylation (Abcam cat# ab21623) in the immunofluorescence assay.

Example 109 In Vivo Tumor Efficacy Model

Female NCr-Nude mice (age 6-8 weeks, Charles River Labs) are aseptically injected into the subcutaneous space in the right dorsal flank with 1.0-5.0×10⁶ cells (SKOV-3, HCT-116, BxPC3) in 100 μL of a 1:1 ratio of serum-free culture media (Sigma Aldrich) and BD Matrigel™ (BD Biosciences) using a 1 mL 26⅜ gauge needle (Becton Dickinson Ref#309625). Alternatively, some xenograft models require the use of more immunocompromised strains of mice such as CB-17 SCID (Charles River Labs) or NOD-SCID (Jackson Laboratory). Furthermore, some xenograft models require serial passaging of tumor fragments in which small fragments of tumor tissue (approximately 1 mm³) are implanted subcutaneously in the right dorsal flank of anesthetized (3-5% isoflourane/oxygen mixture) NCr-Nude, CB-17 SCID or NOD-SCID mice (age 5-8 weeks, Charles River Labs or Jackson Laboratory) via a 13-ga trocar needle (Popper & Sons 7927). Tumor volume is monitored twice weekly with Vernier calipers. The mean tumor volume is calculated using the formula V=W²×L/2. When the mean tumor volume is approximately 200 mm³, the animals are randomized into treatment groups of ten animals each. Drug treatment typically includes the test compound as a single agent, and may include combinations of the test compound and other anticancer agents. Dosing and schedules are determined for each experiment based on previous results obtained from pharmacokinetic/pharmacodynamic and maximum tolerated dose studies. The control group will receive vehicle without any drug. Typically, test compound (100-200 μL) is administered via intravenous (27-ga needle), oral (20-ga gavage needle) or subcutaneous (27-ga needle) routes at various doses and schedules. Tumor size and body weight are measured twice a week and the study is terminated when the control tumors reach approximately 2000 mm³, and/or if tumor volume exceeds 10% of the animal body weight or if the body weight loss exceeds 20%.

The differences in tumor growth trends over time between pairs of treatment groups are assessed using linear mixed effects regression models. These models account for the fact that each animal is measured at multiple time points. A separate model is fit for each comparison, and the areas under the curve (AUC) for each treatment group are calculated using the predicted values from the model. The percent decrease in AUC (dAUC) relative to the reference group is then calculated. A statistically significant P value suggests that the trends over time for the two treatment groups are different.

The tumor measurements observed on a date pre-specified by the researcher (typically the last day of treatment) are analyzed to assess tumor growth inhibition. For this analysis, a T/C ratio is calculated for each animal by dividing the tumor measurement for the given animal by the mean tumor measurement across all control animals. The T/C ratios across a treatment group are compared to the T/C ratios of the control group using a two-tailed Welch's t-test. To adjust for multiplicity, a False Discovery Rate (FDR) is calculated for each comparison using the approach described by Benjamini and Hochberg, J.R. Stat. Soc. B 1995, 57:289-300.

As detailed above, compounds of the invention inhibit HDAC6. In certain embodiments, compounds of the invention inhibit HDAC6 with an IC50 value of less than 50 nM including compounds: 1, 2, 3, 4, 5, 6, 7, 8, 11, 13, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 40, 42, 51, 54, 64, 65, 67, 68, 76, 80, 88, 89, 94, 95, 98, 99, 103, 107, 116, 127, 131, 132, 133, 139, 140, 146, 152, 156, 159, 163, 169, 171, 176, 177, 179, 184, 186, 187, 188, 193, 194, 205, 209, 212, 231, 233.

In certain embodiments, compounds of the invention inhibit HDAC6 with an IC50 value of greater than 50 nM and less than 100 nM including compounds: 9, 10, 15, 29, 47, 48, 52, 62, 75, 81, 100, 125, 149, 178, 182, 199, 216, 221, 225, 230.

In certain embodiments, compounds of the invention inhibit HDAC6 with an IC50 value of greater than 100 nM and less than 1 μM including compounds: 36, 69, 93, 106, 189, 191, 197, 200, 201, 202, 203, 204, 206, 207, 208, 211, 213, 215, 217, 219, 223, 226, 227, 228, 229, 232.

In certain embodiments, compounds of the invention inhibit HDAC6 with an IC50 value of greater than 1 μM including compounds: 12, 17, 56, 111, 190, 192, 195, 196, 198, 210, 214, 218, 220, 222, 224, 234.

As detailed above, compounds of the invention are selective for HDAC6 over other Class I HDAC enzymes. In some embodiments, the ratio of HDAC IC50 (as obtained in the nuclear extract assay described above) to HDAC6 IC50 is 10:1. In certain embodiments, the ratio of HDAC IC50 to HDAC6 IC50 is 100:1. In certain embodiments, the ratio of HDAC IC50 to HDAC6 IC50 is 1000:1.

While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments, which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments, which have been represented by way of examples. 

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: p is 0-2; q is 1-3; provided that the total of p and q is 1-3; G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₂—R³, -L₁-R³, or -L₁-V₂-L₂-R³; L₁ and L₂ are each independently unsubstituted or substituted C₁₋₃ alkylene, where one carbon atom may be replaced with —CR^(A)═CR^(A)—. V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—; V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—; R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(A) is independently hydrogen, halo, or unsubstituted or substituted C₁₋₄ aliphatic; each occurrence of R^(4a) is independently hydrogen, or unsubstituted or substituted C₁₋₄ aliphatic; R¹ is hydrogen, halo, —CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, —O—C₁₋₃ alkyl, —O—C₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, or NHS(O)₂C₁₋₃ alkyl; ring A is optionally further substituted with n occurrences of R²; each occurrence of R² is independently halo, C₁₋₄ aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or a C₁₋₄ aliphatic substituted with R^(D), halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(B), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C); or two R² are taken together to form a 3-6 membered cycloaliphatic ring; each occurrence of R^(B) is independently H or C₁₋₄ aliphatic; or two R^(B) on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, O and S; each occurrence of R^(C) is independently C₁₋₄ aliphatic; each occurrence of R^(D) is independently 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and n is 0-4.
 2. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: p is 0-2; q is 1-3; provided that the total of p and q is 1-3; G is —R³, —V₁—R³, —V₁-L₁-R³, -L₁-V₁—R³, -L₂-V₂—R³, —V₁-L₁-V₂—R³, or -L₁-R³; L₁ is unsubstituted or substituted C₁₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—; L₂ is unsubstituted or substituted C₂₋₃ alkylene chain, where one carbon atom may be replaced with —CR^(A)═CR^(A)—; V₁ is —C(O)—, —C(S)—, —C(O)—N(R^(4a))—, —C(O)—O—, or —S(O)₂—; V₂ is —C(O)—, —C(S)—, —N(R^(4a))—, —C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —C(O)—O—, —O—C(O)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R^(4a))—C(O)—N(R^(4a))—, —N(R^(4a))—C(O)—O—, —O—C(O)—N(R^(4a))—, or —N(R^(4a))—SO₂—N(R^(4a))—, R³ is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(A) is independently hydrogen, fluoro, or unsubstituted or substituted C₁₋₄ aliphatic; each occurrence of R^(4a) is independently hydrogen, or an optionally substituted C₁₋₄ aliphatic group; R¹ is hydrogen, chloro, fluoro, —O—C₁₋₄ alkyl, cyano, hydroxy, C₁₋₄ alkyl, or C₁₋₄ fluoroalkyl; ring A is optionally further substituted with n occurrences of R²; each occurrence of R² is independently fluoro, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or R^(D); or two R² are taken together to form a 3-6 membered cycloaliphatic ring; each occurrence of R^(D) is independently unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0-4.
 3. The compound of claim 2, wherein: R¹ is hydrogen or methyl; each occurrence of R² is independently fluoro, methyl, or trifluoromethyl; V₁ is —C(O)—, —C(O)—N(R^(4a)), or —S(O)₂—; V₂ is —N(R^(4a))—, —C(O)—NR^(4a)—N(R^(4a))—C(O)—, —SO₂—N(R^(4a))—, —N(R^(4a))—SO₂—, —O—, or —S—; and n is 0-2.
 4. The compound of claim 2, represented by formulas (II-A)-(II-F):


5. The compound of claim 2, wherein: R³ when substituted is substituted with 1-4 independent occurrences of —R⁵, wherein R⁵ is —R^(5a), —R^(5d), -L₃-R^(5d), or —V₃-L₃-R^(5d); each occurrence of R^(5a) is independently halogen, C₁₋₄ aliphatic, —CN, —NO₂, —N(R⁵)₂, —OR^(5b), —SR^(5b), —S(O)₂R^(5c), —S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5e), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂, or a C₁₋₄ aliphatic substituted with R^(5dd), halogen, —CN, —NO₂, —N(R^(5b))₂, —OR^(5b), —SR^(5c), —S(O)₂R^(5c), —S(O)R^(5c)—C(O)R^(5b), —C(O)OR^(5b), —C(O)N(R^(5b))₂, —S(O)₂N(R^(5b))₂, —OC(O)N(R^(5b))₂, —N(R^(5e))C(O)R^(5b), —N(R^(5e))SO₂R^(5e), —N(R^(5e))C(O)OR^(5b), —N(R^(5e))C(O)N(R^(5b))₂, or —N(R^(5e))SO₂N(R^(5b))₂; each occurrence of R^(5b) is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R^(5b) on the same nitrogen atom can be taken together with the nitrogen atom to which they are bound to form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur; each occurrence of R^(5c) is independently an optionally substituted group selected from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(5d) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(5dd) is an optionally substituted group selected from 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R^(5e) is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; each occurrence of V₃ is independently —N(R^(5e)), —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(5e))—, —S(O)₂N(R^(5e))—, —OC(O)N(R^(5e))—, —N(R^(5e))C(O)—, —N(R^(5e))SO₂—, —N(R^(5e))C(O)O—, —N(R^(5e))C(O)N(R^(5e))—, —N(R^(5e))SO₂N(R^(5e))—, —OC(O)—, or —C(O)N(R^(3e))O—; and L₃ is an optionally substituted C₁₋₃ alkylene chain, where one carbon atom may be replaced with CR^(A)═CR^(A)—.
 6. The compound of claim 5, wherein: G is —R³, —C(R⁶)(R^(6′))—R³, —C(O)—R³, or —S(O)₂—R³; R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group; R³ is —R^(3a); and R^(3a) is unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3a) if substituted is substituted with 0-1 occurrences of —R^(5a), and one occurrence of —R^(5d).
 7. The compound of claim 6, represented by formulas (II-A)-(II-C):

wherein: R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; each occurrence of R² is independently fluoro, methyl, or trifluoromethyl; n is 0-2; R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl; R^(5d) if substituted is substituted with 0-2 occurrences of —R^(7a); and each occurrence of R^(7a) is independently chloro, fluoro, bromo, iodo, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆ alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl.
 8. The compound of claim 7, represented by formulas (II-A)-(II-B):


9. The compound of claim 7, wherein: R¹ is hydrogen or methyl; and n is
 0. 10. The compound of claim 7, wherein: R^(5d) is thienyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl, pyrimidinyl, or benzothienyl.
 11. The compound of claim 5, wherein: G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—NH—[C(R⁶)(R^(6′))]_(z)—R³, —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³, —[C(R⁶)(R^(6′))]_(z)—V_(2a)—R³, —C(O)—[C(R⁶)(R^(6′))]_(y)—V_(2a)—R³, —C(R⁶)(R^(6′))—V_(2a′)—R³, or —C(O)—C(R⁶)(R^(6′))—V_(2a)—R³; R⁶ is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; R^(6′) is hydrogen, C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, or 6-10-membered aryl; or R⁶ and R^(6′) are taken together to form a C₃₋₆ cycloaliphatic group; V_(2a) is —C(O)—, —O—, —S—, —N(R^(4a))—, or —C(O)N(R^(4a))—; V_(2a′) is —O—, —S—, or —N(R^(4a))—; R³ is —R^(3d); R^(3d) is unsubstituted or substituted C₁₋₆ aliphatic, unsubstituted or substituted 3-10-membered cycloaliphatic, unsubstituted or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted 6-10-membered aryl, or unsubstituted or substituted 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R^(3d) if substituted is substituted with 0-2 independent occurrences of —R^(5a); z is 0-3; and y is 1-2.
 12. The compound of claim 11, represented by formula (II-A)-(II-C):

wherein: R¹ is hydrogen, chloro, fluoro, methoxy, cyano, or methyl; each occurrence of R² is independently fluoro, methyl, or trifluoromethyl; n is 0-2; R^(3d) is unsubstituted or substituted with 0-1 occurrences of —R^(5a); and R^(5a) is chloro, fluoro, C₁₋₄ alkyl, C₁₋₆ fluoroalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ fluoroalkyl, cyano, hydroxy, —NHC(O)C₁₋₆ alkyl, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆alkyl)₂, —NHC(O)NHC₁₋₆ alkyl, —NHC(O)N(C₁₋₆alkyl)₂, or —NHS(O)₂C₁₋₆ alkyl.
 13. The compound of claim 12, represented by formulas (II-A)-(II-B):


14. The compound of claim 12, wherein: R¹ is hydrogen or methyl; and n is
 0. 15. The compound of claim 12, wherein: R^(5a) is chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or hydroxy.
 16. The compound of claim 12, wherein: G is —[C(R⁶)(R^(6′))]_(z)—R³, —C(O)—[C(R⁶)(R^(6′))]_(z)—R³, or —S(O)₂—[C(R⁶)(R^(6′))]_(z)—R³.
 17. A pharmaceutical composition comprising a compound of claim 1 or 2, and a pharmaceutically acceptable carrier.
 18. A method of treating a proliferative disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or
 2. 19. The method of claim 18, wherein the proliferative disorder is breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute myeloid leukemia, or acute lymphoblastic leukemia.
 20. A method for inhibiting HDAC6 activity in a patient comprising administering a pharmaceutical composition comprising an amount of a compound of claim 1 or 2 effective to inhibit HDAC6 activity in the patient. 